Compositions of a polyorthoester and an aprotic solvent

ABSTRACT

Delivery systems and compositions comprised of a biodegradable polyorthoester polymer, an aprotic solvent, and a drug are described. The solvent is selected to modulate release of drug from the composition, where, in some embodiments, the solvent is rapidly released after administration and provides a corresponding rapid rate of drug release. Alternatively, in other embodiments, the solvent is slowly released from the composition after its administration, and provides a correspondingly slow rate of drug release.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/514,860, filed Jul. 17, 2019, now allowed, which is a continuation ofU.S. application Ser. No. 15/457,545, filed Mar. 13, 2017, now U.S. Pat.No. 10,398,686, issued Sep. 3, 2019, which is a continuation of U.S.application Ser. No. 14/210,318, filed Mar. 13, 2014, now U.S. Pat. No.9,592,227, issued Mar. 14, 2017, which claims the benefit of priority ofU.S. Provisional Patent Application No. 61/789,469 filed Mar. 15, 2013,and of U.S. Provisional Patent Application No. 61/902,018 filed Nov. 8,2013, the contents of each are incorporated herein by reference.

TECHNICAL FIELD

The present disclosure is directed to compositions, systems and methodscomprised of a biodegradable polyorthoester polymer, an aprotic solvent,and a drug.

BACKGROUND

Polymer-based depot systems for administering an active agent are wellknown. These systems incorporate the active agent into a carriercomposition, such as a polymeric matrix, from which the active agent isdelivered upon administration of the composition to a patient.

Many factors influence the design and performance of such systems, suchas the physical/chemical properties of the drug, the physical/chemicalcharacteristics of the system's components and the performance/behaviorrelative to other system components once combined, as well asexternal/environmental conditions at the site of application. Indesigning polymer-based systems for delivery of a drug, the desired rateof drug delivery and onset, the drug delivery profile, and the intendedduration of delivery all must be considered.

There remains a need for polymer-based compositions that offer theflexibility to modulate or tailor the rate of drug release. The presentsystems, compositions, and related methods satisfy this need.

BRIEF SUMMARY

In one aspect, i.e., a first aspect, a delivery system comprised of apolyorthoester, an aprotic solvent in which the polyorthoester ismiscible to form a single phase; and a therapeutically active agentdispersed or solubilized in the single phase is provided. The activeagent is released from the system over a period of between approximately1 day and approximately 8 weeks.

In one embodiment, related to any one or more of the aspects or otherembodiments provided herein, the delivery system has a viscosity of lessthan about 10,000 cP at 37° C.

In another embodiment, the solvent is an organic solvent having a watersolubility of greater than 25% by weight of the solvent in water at roomtemperature.

In yet another embodiment, the solvent is a dipolar aprotic solvent.

In still another embodiment, the solvent is in a class selected from thegroup consisting of an amide, a biocompatible oil, an ester of an acid,an ester of an alcohol, an ether, a ketone, a sulfoxide, a triglyceride,and an ester of a triglyceride.

In one embodiment, the solvent is an amide selected from the groupconsisting of 2-pyrrolidone, dimethyl formamide, N-methyl-2-pyrrolidone,N-ethyl-2-pyrrolidone, dimethyl acetamide, n-cyclohexyl-2-pyrrolidoneand caprolactam.

In another embodiment, the solvent is a biocompatible oil, excludingnon-hydrogenated vegetable oils, partially-hydrogenated vegetable oils,peanut oil, sesame oil or sunflower oil.

In still another embodiment, the solvent is an ester of an acid selectedfrom the group consisting of carboxylic acid esters and fatty acidesters, excluding propylene glycol dicaprate and propylene glycoldicaprylate.

In yet another embodiment, the solvent is selected from the groupconsisting of ethyl acetate, benzyl benzoate, methyl acetate, isopropylmyristate, ethyl oleate, methyl lactate and ethyl lactate.

In another embodiment, the solvent is an ester of an alcohol, and ispropylene carbonate (4-methyl-1,3-diololan-2-one).

In one embodiment, the solvent is an ether selected from dimethylisosorbide and tetrahydrofuran.

In another embodiment, the solvent is a ketone selected from the groupconsisting of acetone and methyl ethyl ketone.

In still another embodiment, the solvent is a lactone selected from thegroup consisting of caprolactone and butyrolactone.

In yet another embodiment, the solvent is a sulfoxide selected from thegroup consisting of dimethyl sulfoxide and decylmethylsulfoxide.

In one embodiment, the solvent is 1-dodecylazacycloheptan-2-one.

In another embodiment, the solvent is not propylene glycol dicaprate,propylene glycol dicaprylate, glycofurol, a non- orpartially-hydrogenated vegetable oil, glyceryl caprylate, glycerylcaprate, glyceryl caprylate/caprate, glyceryl 10caprylate/caprate/laurate, poly(ethylene glycol-copolypropylene glycol,poly(ethylene glycol)monomethyl ether 550, poly(ethylene glycol)dimethylether 250, glycerine triacetate, or a triglyceride.

In one embodiment, the therapeutically active agent is an anti-emetic.

In another embodiment, the therapeutically active agent is ananesthetic, such as, for example, a local amide- or anilide-typeanesthetic. Representative compounds include bupivacaine,levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine,tetracaine, and ropivacaine.

In an embodiment related to the foregoing, the therapeutically activeagent is ropivacaine or bupivacaine.

In a further embodiment, the therapeutically active agent is asemi-synthetic opioid.

In another embodiment, the polyorthoester is selected from thepolyorthoesters represented by Formulas I, II, III and IV set forthherein below.

In yet a further embodiment, the polyorthoester is represented byFormula III as set forth herein.

In yet a further embodiment, the polyorthoester is represented by thestructure shown as Formula III,

where A is R¹ or R³,where R¹ is:

where p and q are integers that vary from between about 1 to 20 and theaverage number of p or the average of the sum of p and q is between 1and 7;R³ and R⁶ are each independently:

where x is an integer of 0 to 30;where A is R¹ in 0 to 20% of the monomeric units of the polyorthoester.

In yet another embodiment related to the polyorthoester, thepolyorthoester has a molecular weight between about 1,000 and 10,000daltons.

In one embodiment, the polyorthoester is represented by the structureshown as Formula III, the active agent is granisetron in an amountbetween 1-5 percent by weight of the delivery system, and the solvent isDMSO in an amount between 10-35 percent by weight of the deliverysystem.

In a particular embodiment, the delivery system comprises the aproticsolvent in an amount between 15-50 percent by weight of the deliverysystem, and the therapeutic agent is in an amount between 3 and 30percent by weight of the delivery system.

In yet another embodiment, the polyorthoester is represented by thestructure shown as Formula III in accordance with any one or more of thecombinations and sets of variables related thereto as provided herein;the active agent is ropivacaine or bupivacaine in an amount between 3and 30 percent by weight of the delivery system, and the solvent isselected from dimethyl sulfoxide, dimethyl acetamide and N-methylpyrrolidone in an amount between 15-50 percent by weight of the deliverysystem.

In another or second aspect, a flowable composition comprised of apolyorthoester, a solvent in which the polyorthoester is miscible toform a single phase; and a therapeutically active agent dispersed orsolubilized in the single phase, wherein the solvent is an aproticsolvent with a dipole moment greater than about 2 Debye (D), isprovided.

In one embodiment, the solvent is an ester of an alcohol, propylenecarbonate (4-methyl-1,3-diololan-2-one).

In another embodiment, the solvent is a ketone selected from the groupconsisting of acetone and methyl ethyl ketone.

In yet another embodiment, the solvent an amide selected from the groupconsisting of 2-pyrrolidone, dimethyl formamide, N-methyl-2-pyrrolidone,and dimethyl acetamide.

In still another embodiment, the solvent is a sulfoxide selected fromthe group consisting of dimethyl sulfoxide and decylmethylsulfoxide.

In one embodiment, the solvent is an ether selected from dimethylisosorbide and tetrahydrofuran.

In one embodiment, the solvent is a lactone selected from the groupconsisting of ester-caprolactone and butyrolactone.

The composition, in any embodiment, can comprise as the therapeuticallyactive agent an anti-emetic.

Alternatively, in any embodiment, the composition can comprise as thetherapeutically active agent an anesthetic, such as, e.g., ropivacaineor bupivacaine, or another “caine”-type anesthetic.

Further, the composition, in any embodiment, can comprise as thetherapeutically active agent, an opioid such as buprenorphine.

The composition, in any embodiment, can comprise as the polyorthoester apolyorthoester selected from the group represented by Formulas I, II,III and IV set forth herein below.

The composition, in any embodiment, can comprise a viscosity of lessthan about 10,000 cP at 37° C.

In one embodiment, the polyorthoester is represented by the structureshown as Formula III, the active agent is granisetron in an amountbetween 1-5 percent by weight of the composition, and the solvent isDMSO in an amount between 10-35 percent by weight of the composition.

In another aspect, a method of administering a therapeutically activeagent is provided. The method comprises dispensing from a needle adelivery system or a composition as described herein.

In another aspect, provided is a method of treatment comprisingdispensing from a needle a composition comprised of a polyorthoester, anaprotic solvent in which the polyorthoester is miscible to form a singlephase; and a therapeutically active agent dispersed or solubilized inthe single phase; wherein the solvent is selected to achieve acontrolled release of the active agent from the composition according toa predetermined release profile, and wherein the release of the activeagent is for a period of between approximately 1 day and approximately 8weeks.

In one embodiment, the solvent is selected to have a dipole momentgreater than about 2 Debye (D).

In another embodiment, the composition has a viscosity of less thanabout 10,000 cP at 37° C.

Additional embodiments of the present systems, compositions and methodswill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims, particularly when considered in conjunction with theaccompanying examples and drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1B are graphs of the percent of solvent released as a functionof time, in hours, from a delivery system comprised of a polyorthoesterand an aprotic solvent, dimethylsulfoxide (DMSO, FIG. 1A) or dimethylacetamide (DMAC, FIG. 1B), in an in vitro dissolution apparatus, wherein FIG. 1A the compositions comprised 30% DMSO (diamonds), 40% DMSO(squares) and 50% DMSO (triangles), and in FIG. 1B the compositionscomprised 20% DMAC (diamonds), 30% DMAC (squares), 40% DMAC (triangles),or 50% DMAC (x symbols);

FIGS. 2A-2B are graphs of the percent of active agent, granisetron,released as a function of time, in hours, from a delivery systemcomprised of a polyorthoester and an aprotic solvent, dimethylsulfoxide(DMSO, FIG. 2A) or dimethyl acetamide (DMAC, FIG. 2B), in an in vitrodissolution apparatus;

FIG. 3A is a bar graph showing the percent of active agent, granisetron,released at 24 hours in an in vitro dissolution release test, fromcompositions comprised of a polyorthoester and an aprotic solvent,dimethylsulfoxide (DMSO, open bars), dimethyl acetamide (DMAC, hatchedbars) or N-methyl-2-pyrrolidone (NMP, dotted bars);

FIGS. 3B-3C are bar graphs showing the percent of active agent,granisetron, released after 24 hours (FIG. 3B) and 72 hours (FIG. 3C) inan in vitro dissolution release test, from compositions comprised of apolyorthoester and varying percentages, 10%, 20%, 30%, 40% or 50% of anaprotic solvent, dimethylsulfoxide (DMSO);

FIG. 4 is a graph of the percent of active agent, granisetron, releasedas a function of time, in hours, from a delivery system comprised of apolyorthoester and an aprotic solvent, dimethyl isosorbide atconcentrations in the system of 19.6 wt % (diamonds) and 9.8 wt %(squares);

FIG. 5 is a graph of plasma concentration of granisetron, in ng/mL, as afunction of time, in hours, for a delivery system comprised of apolyorthoester, granisetron, and 26.5 wt % of DMSO (squares) or 34.3 wt% DMSO;

FIG. 6 is a graph of plasma concentration of ropivacaine, in ng/mL, indogs, as a function of time, in hours, for various exemplary deliverysystems comprising a polyorthoester, ropivacaine, and an aprotic solventas described in Example 9. Data is provided for Formulation No. 07-03(diamonds) comprised of 75.0 wt % polyorthoester, ropivacaine (4.75 wt %free base, 0.25 wt % HCl salt), 25.0 wt % N-methyl-2-pyrrolidone (NMP);Formulation No. 07-04 (squares) comprised of 56.4 wt % polyorthoester,20.70 wt % ropivacaine free base, 22.9 wt % dimethyl acetamide (DMAc);Formulation No. 07-05 (circles) comprised of 45.0 wt % polyorthoester,10.00 wt % ropivacaine free base, 45.0 wt % N-methyl-2-pyrrolidone; andFormulation No. 07-06 (triangles) comprised of 71.0 wt % polyorthoester,ropivacaine (4.50 wt % free base, 0.50 wt % HCl salt), and 24.0 wt %N-methyl-2-pyrrolidone; and

FIG. 7 is a graph of plasma concentration of bupivacaine, in ng/mL, indogs, as a function of time, in hours, for two exemplary deliverysystems comprising a polyorthoester, bupivacaine, and an aprotic solventas described in Example 12. Data is shown for Formulation No. 02-01comprised of 55.0 wt % polyorthoester, 15.0 wt % bupivacaine, and 30.0wt % N-methyl-2-pyrrolidone (NMP); and for Formulation No. 02-02comprised of 42.5 wt % polyorthoester, 15.0 wt % bupivacaine, and 42.5wt % N-methyl-2-pyrrolidone.

DETAILED DESCRIPTION I. Definitions

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to a “polymer” includes a single polymer aswell as two or more of the same or different polymers, reference to an“excipient” includes a single excipient as well as two or more of thesame or different excipients, and the like.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

“Molecular mass” in the context of a polymer such as a polyorthoester,refers to the nominal average molecular mass of a polymer, typicallydetermined by size exclusion chromatography, light scatteringtechniques, or velocity. Molecular weight can be expressed as either anumber-average molecular weight or a weight-average molecular weight.Unless otherwise indicated, all references to molecular weight hereinrefer to the weight-average molecular weight. Both molecular weightdeterminations, number-average and weight-average, can be measured usinggel permeation chromatographic or other liquid chromatographictechniques. Other methods for measuring molecular weight values can alsobe used, such as the measurement of colligative properties (e.g.,freezing-point depression, boiling-point elevation, or osmotic pressure)to determine number-average molecular weight or the use of lightscattering techniques, ultracentrifugation or viscometry to determineweight-average molecular weight. The polymers of the invention aretypically polydisperse (i.e., number-average molecular weight andweight-average molecular weight of the polymers are not equal),possessing low polydispersity values such as less than about 1.2, lessthan about 1.15, less than about 1.10, less than about 1.05, and lessthan about 1.03. It should be noted that certain properties of polymers,e.g., a polyorthoester, such as molecular weight, molecular number,number of monomer subunits (typically indicated by the subscript belowbrackets enclosing a monomeric subunit of the polymer), and the like,are generally described herein in terms of discrete values, however itwill be understood by those of skill in the art that. because of thecomplex nature of polymers, such values generally refer to averagevalues.

“Bioerodible”, “bioerodibility” and “biodegradable”, which are usedinterchangeably herein, refer to the degradation, disassembly ordigestion of a polymer by action of a biological environment, includingthe action of living organisms and most notably at physiological pH andtemperature. As an example, a principal mechanism for bioerosion of apolyorthoester is hydrolysis of linkages between and within the units ofthe polyorthoester.

As used herein, the term “emesis” includes nausea and vomiting.

Solubility values of solvent in water are considered to be determined at20° C.

A “polymer susceptible to hydrolysis” such as a polyorthoester polymerrefers to a polymer that is capable of degradation, disassembly ordigestion through reaction with water molecules. Such a polymer containshydrolyzable groups in the polymer. Examples of polymers susceptible tohydrolysis may include, but is not limited to, polymers describedherein, and those described in U.S. Pat. Nos. 4,079,038, 4,093,709,4,131,648, 4,138,344, 4,180,646, 4,304,767, 4,957,998, 4,946,931,5,968,543, 6,613,335, and 8,252,304, and U.S. Patent Publication No.2007/0265329, which are incorporated by reference in their entirety.

“Pharmaceutically acceptable salt” denotes a salt form of a drug havingat least one group suitable for salt formation that causes nosignificant adverse toxicological effects to the patient. Reference toan active agent as provided herein is meant to encompass itspharmaceutically acceptable salts, as well as solvates and hydratesthereof. Pharmaceutically acceptable salts include salts prepared byreaction with an inorganic acid, an organic acid, a basic amino acid, oran acidic amino acid, depending upon the nature of the functionalgroup(s) in the drug. Suitable pharmaceutically acceptable salts includeacid addition salts which may, for example, be formed by mixing asolution of a basic drug with a solution of an acid capable of forming apharmaceutically acceptable salt form of the basic drug, such ashydrochloric acid, iodic acid, fumaric acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid,sulfuric acid and the like. Typical anions for basic drugs, when inprotonated form, include chloride, sulfate, bromide, mesylate, maleate,citrate and phosphate. Suitably pharmaceutically acceptable salt formsare found in, e.g., Handbook of Pharmaceutical Salts: Properties,Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002; P. H. Stahl andC. G. Wermuth, Eds.

“Polyorthoester-compatible” refers to, in one particular aspect of theproperties of the polyorthoester, the properties of an additive orcomponent or solvent which, when mixed with the polyorthoester, forms asingle phase and does not cause any physical or chemical changes to thepolyorthoester.

A “therapeutically effective amount” means the amount that, whenadministered to an animal for treating a disease, is sufficient toeffect treatment for that disease.

“Treating” or “treatment” of a disease or condition includes preventingthe disease from occurring in an animal that may be predisposed to thedisease but does not yet experience or exhibit symptoms of the disease(prophylactic treatment), inhibiting the disease (slowing or arrestingits development), providing relief from the symptoms or side-effects ofthe disease (including palliative treatment), and relieving the disease(causing regression of the disease).

Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

The term “substantially” in reference to a certain feature or entitymeans to a significant degree or nearly completely (i.e. to a degree of85% or greater) in reference to the feature or entity.

The term “about”, particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

II. Delivery System and Composition

The systems and compositions described herein comprise a biodegradablepolyorthoester polymer combined with a biocompatible organic solvent,and find use, for example, as drug delivery systems or as medical orsurgical devices. As will be described herein, the selection of solventor solvents in the system may be used to modulate the release profile ofan active agent from the system. The system, in one embodiment, forms alow viscosity solution that can be easily injected into the body withstandard syringes and small gauge needles. In this regard, and as willbe described, the selection of solvent may be used to modulate theviscosity of the composition while minimally altering the releasekinetics of the active agent from the composition. In anotherembodiment, the selection of the solvent is used to modulate the releasekinetics of the active agent from the composition without significantlyaltering the viscosity of the formulation.

Studies were performed that illustrate modulation of release of solventand active agent from a polyorthoester delivery system. In one study, asdetailed in Example 1, compositions comprised of a polyorthoesterpolymer, granisetron base, and an aprotic solvent were prepared, usingas exemplary solvents dimethyl sulfoxide (DMSO) and dimethyl acetamide(DMAC). The release of solvent from the composition was measured in anin vitro dissolution release apparatus, and the results are shown inFIGS. 1A-1B.

FIG. 1A shows the percent of DMSO released as a function of time, inhours, for the compositions with 30% DMSO (diamonds), 40% DMSO (squares)and 50% DMSO (triangles). FIG. 1B shows the percent DMAC released as afunction of time, in hours, for the compositions with 20% DMAC(diamonds), 30% DMAC (squares), 40% DMAC (triangles), or 50% DMAC (xsymbols). As can be seen, the solvent DMSO is released at a slower ratethan DMAC from the compositions, indicating the solvents interact withthe polyorthoester differently. For example, a composition with 30% DMSOreleased about 30% of the solvent at the 24 hour time point, whereas acomposition comprised of DMAC released about 79% of the solvent at the24 hour time point. This finding can be utilized to modulate release ofan active agent from the compositions as provided herein in severalways. For example, an active agent that is soluble in an aprotic solventthat is released from the composition rapidly will provide for releaseof the active agent at a rate similar to the release of the solvent,assuming that the active agent does not alter the interaction of thesolvent and the polymer. An active agent that is less soluble in anaprotic solvent that is released from the composition rapidly willrelease from the composition at a rate different from, and perhapsslower than, the rate of solvent release, particularly if the activeagent is more soluble in the polymer than in the aprotic solvent. Thedata also illustrates the concept of solvent selection to tailor ormodulate active agent release from a composition, in that if an activeagent is equally soluble in two different solvents, the rate of releaseof active agent from the system can be tailored by selecting the solventthat has a faster or slower rate of release.

These concepts are further illustrated in the study described in Example3. In this study a model drug, granisetron, was included in compositionscomprised of a polyorthoester and an aprotic solvent, using DMSO andDMAC as exemplary solvents. The results are shown in FIGS. 2A-2B. InFIG. 2A, the in vitro release of granisetron from compositionscomprising 30 wt % (triangles), 40 wt % (squares) and 50 wt %(triangles) DMSO is shown. The amount of solvent in the systeminfluences the rate of drug release, where a higher amount of solvent inthe composition achieves a higher drug release rate. This correlation isobserved more strongly at release times of less than about 70 hours.

FIG. 2B shows the in vitro release of granisetron from compositionscomprising 20 wt % (triangles), 30 wt % (squares), 40 wt % (triangles)and 50 wt % (x symbols) DMAC. For compositions with DMAC, the amount ofsolvent in the composition has less influence on the rate of granisetronrelease than was observed in FIG. 2A with DMSO. Compositions of apolyorthoester and 20 wt %, 30 wt % and 40 wt % DMAC released betweenabout 30-40% of the drug at the 24 hour time point, and by 70 hourssubstantially all of the drug (e.g., 80-100%) from the composition wasreleased. This system is an example of a system where rate of solventrelease governs or correlates with rate of drug release. In comparingthe data in FIG. 2B with that of FIG. 2A it is seen that a compositionwith DMSO also provides a system where drug release is correlated withrate of solvent release, however because DMSO is released from thecomposition more slowly than DMAC, the rate of drug release is slower,thus illustrating the versatility of the systems provided herein.

Another study was conducted to evaluate the release of drug fromcompositions comprised of a polyorthoester and the illustrative solventsDMSO, DMAC and NMP. As described in Example 4, compositions wereprepared with varying amounts of solvent, and release of drug wasmeasured in an in vitro release apparatus. FIG. 3A is a bar graphshowing the percent of the drug, granisetron, released after 24 hours inan in vitro release apparatus from the compositions. The compositionswith 20 wt % and 30 wt % solvent show that release of active agent fromthe composition depends on the solvent, where compositions with 20-30 wt% DMSO (open bars) release drug more slowly than compositions with 20-30wt % DMAC (hatched bars), which release drug more slowly thancompositions with 20-30 wt % NMP (dotted bars). Accordingly, in oneembodiment, a composition comprised of a polyorthoester and greater than10 wt % and less than 40 wt % of an aprotic solvent is contemplated,where the rate of drug release from the composition is dependent on theaprotic solvent. As seen, selection of NMP as the aprotic solventprovides a composition that releases drug more rapidly than acomposition comprising either DMAC or DMSO. Selection of DMSO as theaprotic solvent for the composition provides for release of drug moreslowly than a composition comprising the same polymer and drug, butcomprising NMP or DMAC.

In one embodiment, the solvent in the composition remains in thecomposition for the period of drug delivery. Compositions where thesolvent remains associated with the polymer typically provided for arate of drug release that is within about 10%, or 20%, or 30% of therate of solvent release over a time interval of between 2-5 hours, or4-6 hours, 4-8 hours. In another embodiment, the solvent in thecomposition is released from the composition at a rate more rapidly thanthe drug, which remains in the polymer for a time longer than thesolvent. This, second embodiment may be important where an insolubledrug is dispersed in the composition, and then the solvent rapidlyleaving behind the insoluble drug actually slows the release of thedrug.

The data in FIG. 3B illustrates the effect of amount of solvent in acomposition on rate of drug release. Compositions comprised ofpolyorthosester, the drug granisetron, and the exemplary aprotic solventDMSO were prepared, where the percent of solvent in the formulationvaried from 10 wt %-50 wt %. Release of drug was measured in an in vitrorelease apparatus, and the percentage of drug released in the earlyphase, after 24 hours, is shown in FIG. 3B. During this phase therelease of granisetron from the composition is controlled by diffusionand remains relatively constant until a threshold concentration of DMSOis reached, after which, the rate of diffusion of granisetron out of theformulation increases. The percentage of drug released in a later phase,after 72 hours, is shown in FIG. 3C. During this phase the release ofgranisetron from the composition is controlled more by biodegradation ofthe composition. Drug release in this phase depends on a complexinteraction of drug polymer and solvent. For the composition of 2%granisetron base, DMSO and polyorthoester, the slowest rate of releaseat 30% DMSO is observed.

Another delivery system was prepared, as described in Example 4, thatwas comprised of a polyorthoester, the aprotic ether solvent, dimethylisosorbide, and granisetron as the model drug. The systems were preparedwith two concentrations of dimethyl isosorbide—19.6 wt % and 9.6 wt %.Release of drug from the systems was measured in vitro, and the resultsare shown in FIG. 4 . The drug release rate observed at times less thanabout 30 hours was essentially the same for the two systems, with lessthan 30% of the drug released 24 hours after placement in theenvironment of use. The rate of drug release after about 40 hoursincreased, with the system comprising about 20 wt % solvent (diamonds)having a faster rate of release than the system with about 10 wt %solvent (squares).

Accordingly, in one embodiment, the delivery systems and compositionsdescribed herein provide a biphasic release of drug and/or solvent,where in some embodiments, release of drug and/or solvent is diffusioncontrolled at times less than about 48 hours, 24 hours, 6 hours, 5hours, 4 hours, 3 hours, 2 hours and 1 hour after administration into anenvironment of use, and release of drug and/or solvent is controlled byor correlates with the rate of erosion of the polymer at times greaterthan 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 24 hours, and 48hours after administration into an environment of use.

Further exemplary compositions and delivery systems are provided inExample 7. Illustrative compositions as provided therein comprisebetween 45 wt % to 80 wt % polyorthoester of formula III, between 20 wt% and 45 wt % of an aprotic solvent, and between 4 wt % to 22 wt %ropivacaine as the model therapeutic (anesthetic) agent. The aproticsolvents, dimethyl acetamide (DMAC), N-methyl pyrrolidone (NMP), anddimethyl sulfoxide (DMSO) were included in the delivery systemsinvestigated. One composition contained a mixture of DMSO and NMP (4.7%DMSO and 22.5% NMP). A further study, as described in Example 8, wascarried out to evaluate the in-vitro release of the active agent,ropivacaine, from the compositions, when placed in phosphate bufferedsaline at 37° C. Release of active agent was evaluated at 24 hourintervals from 24 hours to 144 hours or more. At 24 hours, thecomposition with the highest percentage of ropivacaine released, 45.26%,was a formulation comprised of 24 wt % of NMP. Although this formulationreleased the greatest percentage of active agent within the first 24hours, the rate of drug release slowed significantly after this point,with cumulative release of drug at only 58.65 percent at 96 hours. Incontrast, a formulation similarly containing NMP as the aprotic solvent,but at 45.2 wt % (nearly twice the amount of the former formulation),released 35.78 percent active agent in the first 24 hours, and hadreleased 86.6 wt % active agent by the 96 hour time point. A formulationcomprising 28.9 wt % of NMP demonstrated a release rate of active agentsimilar to that observed for the 24 wt % NMP formulation. Thus, varyingamounts of a given aprotic solvent impact the release profile of activeagent. A formulation comprised of a mixture of DMSO and NMP as theaprotic solvent exhibited the slowest release of drug, with 8.61 wt %drug released at 24 hours, and only 34.17 wt % drug release at 96 hours.In general, DMSO-containing compositions containing similar amounts ofaprotic solvent release the active agent more slowly than formulationscontaining similar amounts of NMP, while a DMAC-containing formulationreleases active agent more slowly than a corresponding formulationcomprised of similar amounts of NMP. These results are consistent withprevious studies in which it was seen that selection of NMP as theaprotic solvent provides a composition that releases drug more rapidlythan a composition comprising either DMAC or DMSO.

A further study was carried out, as described in Example 11, toinvestigate the in-vitro release of yet another amino-amide anestheticmodel drug, bupivacaine, in a drug delivery system as provided hereincomprising an aprotic solvent. Compositions were prepared containingbetween approximately 42 wt % to 60 wt % of a polyorthoester of formulaIII, between about 30 wt % and 42 wt % of an aprotic solvent, andbetween about 9 wt % and 15 wt % of the anesthetic, bupivacaine. Thecompositions are described generally in Example 10. In this example, NMPwas used as the aprotic solvent, although any aprotic solvent asprovided herein may be used. The study further demonstrates that thecompositions are effective to release active agent over an extendedperiod of time, in this case, over a period of at least 192 hours. Ateach time point, the amount (i.e., percentage) of active agent releasedfrom the formulation containing a smaller weight percentage of activeagent was lower than that of the formulation comprised of a greateramount of active agent.

Additional studies were carried out on delivery systems comprising apolyorthoester, an aprotic solvent, and the semi-synthetic opioid,buprenorphine. In these embodiments, compositions containing between76.2 wt % to 62.1 wt % polyorthoester of formula III, between 30.0 wt %and 42.5 wt % of an aprotic solvent, and between 4.9 and 15 wt % of ssemi-synthetic opioid were prepared. See, e.g., Example 14. In thisstudy, the model solvents DMSO and NMP were used. An in-vitro releasestudy was carried out as described in Example 15. This study furtherdemonstrates that the aprotic-solvent comprising formulations providedherein are effective to provide an extended release of active agent overtime.

The systems and compositions provided herein include a polyorthoesterpolymer. A wide range of polyorthoester polymers are suitable for use inthe systems and compositions provided. For instance, in one embodiment,the compositions and delivery systems described herein are comprised ofa polyorthoester of formula I, formula II, formula III or formula IV:

where:

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;

R* is a C₁₋₄ alkyl;

R^(o), R″ and R′″ are each independently H or C₁₋₄ alkyl;

n is an integer of at least 5; and

A is a diol.

In another alternative embodiment, the compositions and delivery systemsdescribed herein are comprised of a polyorthoester of formula I, formulaII, formula III or formula IV:

where:

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;

R* is a C₁₋₄ alkyl;

R^(o), R″ and R′″ are each independently H or C₁₋₄ alkyl;

n is an integer of at least 5; and

A is R¹, R², R³, or R⁴, where

R¹ is:

where:

p and q are integers that vary from between about 1 to 20 and theaverage number of p or the average of the sum of p and q is between 1and 7 in an least a portion of the monomeric units of the polymer;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:

s is an integer of 0 to 30;

t is an integer of 2 to 200; and

R⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:

x is an integer of 0 to 100;

y is an integer of 2 to 200;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and

R⁴ is the residue of a diol containing at least one functional groupindependently selected from amide, imide, urea, and urethane groups.

Additional polyorthoesters for use herein are those in which, in certainembodiments, A is R¹, R³, or R⁴, where

R¹ is:

where:

p and q are integers that vary from between about 1 to 20 and theaverage number of p or the average of the sum of p and q is between 1and 7 in an least a portion of the monomeric units of the polymer;

R³ and R⁶ are each independently:

where:

x is an integer of 0 to 30;

y is an integer of 2 to 200;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and

R⁴ is a residual of a diol containing at least one functional groupindependently selected from amide, imide, urea and urethane groups; andR⁵ is hydrogen or C₁₋₄ alkyl.

In one or more preferred embodiments, the descriptions of substituents,structures, and variables as set forth in one or more of the embodimentsabove or below relate in particular to the polyorthoester of formulaIII.

In one or more embodiments, the concentration of the polyorthoesterranges from 1% to 99% by weight.

In a particular embodiments, the polyorthoester has a molecular weightbetween 1,000 and 10,000.

In yet another embodiment, the fraction of the A units that are of theformula R¹ is between about 0 and 25 mole percent.

In yet another embodiment, the fraction of the A units that are of theformula R¹ is between about 0 and 10 mole percent.

In yet another embodiment, the fraction of the A units that are of theformula R¹ is between about 0 and 5 mole percent.

In yet another embodiment, the fraction of the A units that are of theformula R¹ is between about 10 and 25 mole percent.

In yet another embodiment, none of the A units are of the formula R¹.

Additional polyorthoesters include, e.g., in another embodiment, apolyorthoester of formula III, where none of the units have A equal toR²;

R³ is:

where

x is an integer of 0 to 10;

y is an integer of 2 to 30; and

R⁶ is:

where:

s is an integer of 0 to 10;

t is an integer of 2 to 30; and

R⁵, R⁷, and R⁸ are independently hydrogen or methyl.

In another embodiment, R³ and R⁶ are both —(CH₂CH₂O)₂(CH₂CH₂)—; R⁵ ismethyl; and p is 1 or 2.

In yet another embodiment of the polyorthoester, R³ and R⁶ are both—(CH₂CH₂O)₉—(CH₂CH₂)—; R⁵ is methyl; and p or the sum of p and q is onaverage 2.

In another variation, the polyorthoester is of formula III, R is—(CH₂)_(b)O(CH₂)_(c)—; where b and c are both 2; R* is a C2 alkyl.

The polyorthoester, as shown in formula I, formula II, formula III andformula IV, in some embodiments, is one of alternating residues of adiketene acetal and a diol, with each adjacent pair of diketene acetalresidues being separated by the residue of one polyol, such as a diol.

Polyorthoesters having a higher mole percentage of the “α-hydroxy acidcontaining” units will have a higher rate of bioerodibility. In onevariation, the polyorthoesters are those in which the mole percentage ofthe “α-hydroxy acid containing” units is at least 0.01 mole percent, inthe range of about 0.01 to about 50 mole percent, from about 0.05 toabout 30 mole percent, for example from about 0.1 to about 25 molepercent, especially from about 1 to about 20 mole percent. The molepercentage of the “α-hydroxy acid containing” units appropriate toachieve the desired composition will vary from formulation toformulation.

In another embodiment, the polyorthoester is one where n is an integerof 5 to 1000; the polyorthoester has a molecular weight of 1000 to20,000, or from 1,000 to 10,000, or from 1000 to 8000; R⁵ is hydrogen ormethyl;

R⁶ is:

where s is an integer of 0 to 10, especially 1 to 4; t is an integer of2 to 30, especially 2 to 10; and R⁷ is hydrogen or methyl;

R³ is:

where x is an integer of 0 to 10, especially 1 to 4; y is an integer of2 to 30, or 2 to 10; and R⁸ is hydrogen or methyl;

R⁴ is selected from the residue of an aliphatic diol of 2 to 20 carbonatoms, or 2 to 10 carbon atoms, interrupted by one or two amide, imide,urea or urethane groups;

the proportion of units in which A is R¹ is about 0-50 mol %, or 0.01-50mol %, or 0.05-30 mol %, or 0.1-25 mol %;

the proportion of units in which A is R² is less than 20%, or less than10%, especially less than 5%, and

the proportion of units in which A is R⁴ is less than 20%, less than10%, or less than 5%.

In one or more additional embodiments, the polyorthoesters used in thepresently disclosed delivery systems and compositions are selected fromformulas III and IV below:

where:

-   -   R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is        an integer from 1 to 10, and b and c are independently integers        from 1-5; R* is a C₁₋₄ alkyl;    -   R⁰, R^(II) and R^(III) are each independently H or C₁₋₄ alkyl;    -   n is an integer of at least 5, for example, from 5 to 1000; and    -   A is R¹, R², R³, or R⁴, where    -   R¹ is:

where:

p is an integer of 1 to 20;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:

s is an integer of 0 to 30;

t is an integer of 2 to 200; and

R⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:

x is an integer of 0 to 100;

y is an integer of 2 to 200;

q is an integer of 2 to 20;

r is an integer of 1 to 20;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R₁₁ and R₁₂together are C₃₋₁₀ alkylene; and

R⁴ is the residue of a diol containing at least one functional groupindependently selected form amide, imide, urea, and urethane groups;

In one preferred embodiment related to the foregoing, the polyorthoesteris described by formula III.

The polyorthoester polymers are prepared, for example, by reaction of adiketene acetal according to one of the following formulas:

where L is hydrogen or a C₁₋₃ alkyl, and R is as defined above, with aat least one diol according to the formulae, HO—R¹—OH, HO—R²—OH,HO—R³—OH, or HO—R⁴—OH (where R¹, R², R³ and R⁴ are as described above).In the presence of water, the α-hydroxy acid containing subunits arereadily hydrolyzed at body temperature and at physiological pH toproduce the corresponding hydroxyacids, which can then act as catalyststo control the hydrolysis rate of the polyorthoester without theaddition of exogenous acid. Thus, polyorthoesters having a higher molepercentage of α-hydroxy acid containing subunits possess a higher degreeof bioerodibility.

Preferred polyorthoesters are those in which the mole percentage ofα-hydroxy acid containing subunits is at least about 0.01 mole percent,although in certain instances, polyorthoesters having no α-hydroxyacid-containing subunits may be employed. Exemplary percentages ofα-hydroxy acid containing subunits in the polymer (e.g.,glycolide-derived subunits) are from about 0 to about 50 mole percent,or from about 0.01 to about 50 mole percent, or from about 0.05 to about30 mole percent, or from about 0.1 to about 25 mole percent. As anillustration, the percentage of α-hydroxy acid containing subunits maybe 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 24, 26, 27, 28, 29 or 30 mol percent, including anyand all ranges lying therein, formed by combination of any one lowermole percentage number with any higher mole percentage number.

In one embodiment, a preferred polyorthoester is one in which R⁵ ishydrogen or methyl; R⁶ is

where s is an integer from 0 to 10, e.g., preferably selected from 1, 2,3, or 4; t is an integer from 2 to 30, particularly selected from 2, 3,4, 5, 6, 7, 8, 9 and 10; R⁷ is hydrogen or methyl; and R³ is

where x is an integer from 0 to 10, e.g., preferably selected from 1, 2,3, or 4; y is an integer from 2 to 30, particularly selected from 2, 3,4, 5, 6, 7, 8, 9 and 10; R⁸ is hydrogen or methyl; R⁴ is selected from aresidue of an aliphatic diol having from 2-20 carbon atoms (e.g.,selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, and 20 carbon atoms), preferably having from 2 to 10 carbonatoms, interrupted by one or two amide, imide, urea, or urethane groups.Preferably, the proportion of subunits in the polyorthoester in which Ais R¹ is from about 0-50 mole percent, or from 0.01-50 mole percent, orfrom about 0.05 to about 30 mole percent, or from about 0.1 to 25 molepercent. Illustrative and preferred mole percentages include 0, 5, 10,15, 25 and 25 mole percent of percentage of subunits in thepolyorthoester in which A is R¹. In one preferred embodiment, the molepercent is about 20. In yet another preferred embodiment, depending onthe selection of the aprotic solvent and the active agent, theproportion of subunits in which A is R² is less than 20 percent,preferably less than about 10 percent, and more preferably less thanabout 5 percent, and the proportion of subunits in which A is R⁴ is lessthan 20 percent, preferably less than about 10 percent and morepreferably less than 5 percent.

An exemplary polyorthoester comprises subunits selected from

where

x is an integer from 1-4 (e.g., can be selected from 1, 2, 3, and 4)

the total amount of p is an integer from 1-20 (e.g., can be selectedfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,and 20),

s is an integer from 1-4 (e.g., can be selected from 1, 2, 3, and 4),

the mole percentage of α-hydroxyacid containing subunits in thepolyorthoester is from about 0 to about 25 mole percent, or from about0.1 to about 25 mole percent, and the polyorthoester has a molecularweight in a range of about 1,000 Da to 10,000 Da.

For example, in one embodiment, the polyorthoester comprises alternatingresidues of3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl:

and a diol-ate residue of triethylene glycol or of triethylene glycoldiglycolide prepared by reacting triethylene glycol with from 0.5 to 10molar equivalents of glycolide at about 100-200° C. for about 12 hoursto 48 hours. Typically, the mole percentage of glycolide-containingsubunits in the polyorthoester is from about 0.1 to about 25 molepercent, and the polyorthoester has a molecular weight of about 1,000 Dato 10,000 Da.

Polyorthoesters such as those described above are prepared by reactingan illustrative diketene acetal,3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU),

with one or more diols as described above, e.g., triethylene glycol(TEG) and triethylene glycol diglycolide (TEGdiGL). Diols such astriethylene diglycolide or triethylene monoglycolide, or the like, areprepared as described in U.S. Pat. No. 5,968,543, e.g., by reactingtriethylene glcol and glycolide under anhydrous conditions to form thedesired product. For example, a diol of the formula HO—R¹—OH comprisinga polyester moiety may be prepared by reacting a diol of the formulaHO—R⁶—OH with between 0.5 and 10 molar equivalents of a cyclic diesterof an α-hydroxy acid such as lactide or glycolide, and allowing thereaction to proceed at 100-200° C. for about 12 hours to about 48 hours.Suitable solvents for the reaction include organic solvents such asdimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile,pyrrolidone, tetrahydrofuran, and methylbutyl ether. Although the diolproduct is generally referred to herein as a discrete and simplifiedentity, e.g., TEG diglycolide (and products such as TEG diglycolide), itwill be understood by those of skill in the art that due to the reactivenature of the reactants, e.g., ring opening of the glycolide, the diolis actually a complex mixture resulting from the reaction, such that theterm, TEG diglycolide, generally refers to the average or overall natureof the product. In a preferred embodiment, the polyorthoester isprepared by reacting DETOSU, triethylene glycol, and triethylene glycoldiglycolide in the following molar ratios: 90:80:20. Thus, in aparticular embodiment, the polyorthoester comprises about 20 molepercent R¹, where R¹ is triethylene glycol diglycolide, and 80 molepercent R³, where R³ is triethylene glycol.

Additional methods of manufacturing the polyorthoesters are well knownin the art.

Solvents for use in the compositions and delivery systems are aproticsolvents, and can be either water miscible, partially water miscible, orpoorly water miscible, depending on the desired release profile for agiven active agent and the solubility of the active agent in thepolyorthoester polymer and polymer/solvent combination. It is alsodesired that the solvent be non-toxic. In one embodiment the solvent isselected such that it will quickly leave the composition after cominginto contact with an aqueous environment, e.g. body fluids. In anotherembodiment, the solvent is selected such that, at least, some of thesolvent will remain in the composition after coming into contact withbody fluids.

In some embodiments a composition is comprised of a drug dissolved in apolymer/hydrophilic (water miscible) solvent combination, and the drugmay be encapsulated or entrapped in the polymer matrix as thehydrophilic solvent dissolves or dissipates from the composition andinto the body fluid. In other embodiments, a composition is comprised ofa lipophilic (poorly water miscible) solvent, and the dissolution ordiffusion of the lipophilic solvent into surrounding aqueous tissuefluid will be relatively slow with a resultant slower increase inviscosity of the administered composition. However, a lipophilicsolvent, by its own nature, may slow the release of active agentincorporated into the composition until the solvent has dissipated,leaving the polymer at the site of delivery with the entrapped activeagent. By adjusting the hydrophilicity/lipophilicity character of thepolymer and/or the solvent, the release of the active agent can becontrolled to provide a low initial burst and sustained release of bothhydrophilic and lipophilic active agents. In addition, the solubility ofa hydrophilic or lipophilic active agent can be controlled to provideeither solutions or dispersions of the active agent in the liquidpolymer/solvent compositions.

Suitable hydrophilic (water miscible) biocompatible organic solventsthat may be used have, in one embodiment, water solubility greater than10% by weight of the solvent in water. Examples of hydrophilicbiocompatible organic solvents include amides such asN-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, N-ethyl-2-pyrrolidone,N-cycylohexyl-2-pyrrolidone, dimethyl acetamide, and dimethyl formamide;esters of monobasic acids such as methyl lactate, ethyl lactate, andmethyl acetate; sulfoxides such as dimethyl sulfoxide anddecylmethylsulfoxide; lactones such as e-caprolactone and butyrolactone;ketones such as acetone and methyl ethyl ketone; and ethers such asdimethyl isosorbide and tetrahydrofuran.

Suitable lipophilic biocompatible organic solvents that may be used inthe compositions and delivery systems described herein have, in oneembodiment, a water solubility less than 10% by weight of the solvent inwater. Examples of lipophilic biocompatible organic solvents includeesters of mono-, di-, and tricarboxylic acids such as ethyl acetate,ethyl oleate and isopropyl myristate; and esters of aromatic acids suchas benzyl benzoate.

Combinations of different hydrophilic solvents can be used to obtainhigher or lower levels of solubility of the liquid polymer and bioactiveagent in the resultant solution. A combination of organic solvents canalso be used to control the rate of release of an active agent bycontrolling the rate at which the solvent dissolves or dissipates whenthe liquid polymer/solvent/active agent composition is placed in thebody. Similarly, combinations of different lipophilic solvents can alsobe used to control the solubility of the liquid polymer and active agentin the solvent and the release of the active agent in the body. In otherembodiments, combinations of hydrophilic and lipophilic solvents can beused to obtain the optimum solvent characteristics for a deliverysystem. Examples include a combination of N-methylpyrrolidone andisopropyl myristate which provides a more hydrophobic solvent thanN-methylpyrrolidone alone, and a combination of N-methylpyrrolidone andanother more soluble organic solvent, to provide a more hydrophilicsolvent combination than N-methylpyrrolidone alone.

In one embodiment, the solvent is not one or more of the followingsolvents: propylene glycol dicaprate, propylene glycol dicaprylate,glycofurol, a non- or partially-hydrogenated vegetable oil, glycerylcaprylate, glyceryl captate, glyceryl caprylate/caprate, glyceryl 10caprylate/caprate/laurate, poly(ethylene glycol-copolypropylene glycol,poly(ethylene glycol)monomethyl ether 550, poly(ethylene glycol)dimethylether 250, glycerine triacetate, or a triglyceride.

The organic solvent is typically added to the compositions in an amountranging from about 10 percent to about 70 percent by weight, relative tothe total weight of the composition. The solvent may be present in thecomposition in an amount ranging from about 20 percent to about 50percent or from about 15 percent to about 40 percent by weight,depending upon the particular solvent, the polyorthoester, active agentand desired release profile of the therapeutic agent. In otherembodiments, the solvent may be present in the composition in an amountranging from about 10-60 wt %, 15-60 wt %, 15-50 wt %, 20-60 wt %, 25-50wt %, 30-70 wt %, 30-60 wt %, 30-50 wt %, 35-70 wt %, 35-60 wt %, 35-50wt %, 10-20 wt %, 15-25 wt %, 20-30 wt %, 15-35 wt %, 20-35 wt % or20-40 wt %. The concentration of solvent allows for the level of polymerin the composition to range from about 30 percent to about 90 percent byweight, or from about 50 percent to about 80 percent by weight relativeto the overall composition.

In other embodiments, the compositions comprise between about 10 percentby weight to about 70 percent by weight solvent, relative to thecombined weight of the polymer and solvent in the composition, or thecompositions may comprise between about 20-50 or 15-40 percent by weightsolvent, relative to the combined weight of the polymer and solvent inthe composition. In other embodiments, the solvent may be present in thecomposition in an amount, relative to the combined amount of polymer andsolvent in the composition, ranging from about 10-60 wt %, 15-60 wt %,15-50 wt %, 20-60 wt %, 25-50 wt %, 30-70 wt %, 30-60 wt %, 30-50 wt %,35-70 wt %, 35-60 wt %, 10-20 wt %, 15-25 wt %, 20-30 wt %, 15-35 wt %,20-35 wt % or 20-40 wt %. The concentration of solvent may allow for thelevel of polymer in the composition to range from about 30 percent toabout 90 percent by weight, or from about 50 percent to about 80 percentby weight relative to weight of the polymer and solvent in thecomposition.

The polymer/solvent concentrations permit the liquid polymer/solventcompositions to be easily injected with standard syringes and smallgauge needles (e.g., about 18-26 gauge) unlike liquid polymerformulations previously described, for example, which in someembodiments, unlike the present compositions, require the addition of aparticulate material to achieve an acceptable viscosity for injectionwith a syringe and needle. The compositions of the invention can beadministered into the body of a human subject or animal such as a dog,cat, horse, etc.

The rate of release of the active agent (e.g., drug) can be controlledby the composition of the biodegradable polymer and/or by thehydrophilicity or lipophilicity of the organic solvent that is used. Thecomposition of the liquid polymer (i.e., the type of monomer used or theratio of monomers for copolymers or terpolymers, the end groups on thepolymer chains, and the molecular weight of the polymer) will determinethe hydrophilicity or lipophilicity of the liquid polymer material aswell as the degradation time of the liquid polymer depot. Morehydrophilic liquid polymers (e.g., polyorthoesters wherein the diolmonomer is hydrophilic, e.g., triethylene glycol, tetraethylene glycol,or polyethylene glycol and the like) and/or more hydrophilic solvents(e.g., N-methyl-2-pyrrolidone) can be used for active agents inapplications where faster release rates and shorter durations of release(e.g., about 1-3 days) are needed. For slower releasing active agentsand where longer durations of release for prolonged delivery (e.g.,about 7-90 days) are desired, more hydrophobic and slower degradingliquid polymers (polyorthoesters wherein the diol monomer ishydrophobic, e.g., 1-6 hexanediol, 1-10 decanediol, or 1-12 dodecandioland the like) and/or more lipophilic solvents (e.g., isopropylmyristate) can be used to that advantage. For even slower rates andlonger durations of release of an active agent, the active agent itselfcan be made more water-insoluble by utilizing active agents, forexample, in the form of lipophilic salts, drug complexes, and/or prodrugesters, amides or ethers. Thus, various forms of the drug can be used asneeded. The composition includes the active agent in an amount effectiveto provide the desired therapeutic effect over the release period. Theconcentration range of the active agent in the composition will vary,for example, according to the active agent, the formulation and the rateof release from the depot, and can range, for example, from about 0.1%to about 30% by weight. The liquid composition releases an effectiveamount of the bioactive agent by diffusion or dissolution from thecomposition as it biodegrades in the body.

While the singular form is used to describe the polyorthoester andsolvent in this application, it is understood that more than onepolyorthoester and/or more than one solvent selected from the groupsdescribed above may be used in the delivery system. In some embodimentsof the above methods, the compositions further comprise an excipient,and in a preferred embodiment the excipient is one that does notinfluence the release of solvent and/or active agent from thecomposition. The concentrations of the polyorthoester and an excipientin the delivery vehicle may vary. For example, the concentration of anexcipient in the vehicle may be in the range of 1-99% by weight, or5-80% weight, or 20-60% by weight of the vehicle. While the singularform is used to describe the polyorthoester and excipient herein, it isunderstood that more than one polyorthoester and excipient may be usedin the delivery system or composition. It is also understood that whilenot required, other pharmaceutically acceptable inert agents such ascoloring agents and preservatives may also be incorporated into thecomposition.

Generally, the excipients are pharmaceutically acceptable andpolyorthoester-compatible materials. In one embodiment, the excipient isa liquid at room temperature, and is readily miscible with thepolyorthoester.

The compositions described herein are easily syringable or injectable,meaning that they can readily be dispensed from a conventional tube ofthe kind well known for topical or ophthalmic formulations, from aneedleless syringe, or from a syringe with a 16 gauge or smaller needle(such as 16-25 gauge), and injected subcutaneously, intradermally orintramuscularly. The formulations may be applied using various methodsknown in the art, including by syringe, injectable or tube dispenser.

Non-limiting examples of preferred aprotic solvents are set forth inTable 1.

TABLE 1 Exemplary Aprotic Solvents Dipole Water Moment Solvent ClassMiscibility (D) 2-pyrrolidone amides 3.5 dimethyl formamide watermiscible 3.86 N-methyl-2-pyrrolidone water miscible 4.09 (NMP)n-ethyl-2-pyrrolidone water miscible 4.1 dimethyl acetamide watermiscible 4.60 N-cyclohexyl-2- poorly miscible pyrrolidone caprolactam(cyclic amide) ethyl acetate esters of a partially miscible 1.84carboxylic acid (8.3 g/100 ml) benzyl benzoate poorly miscible 2.06methyl acetate water miscible 1.75 isopropyl myristate Esters of a fattypoorly miscible ethyl oleate acid poorly miscible methyl lactate Estersof an water miscible ethyl lactate acid (monobasic water miscible acid)propylene carbonate Esters of an water miscible 4.9(4-methyl-1,3-diololan- alcohol 2-one) (polyhydroxy alcohol) dimethylether ethers 1.25 tetrahydrofuran water miscible 1.75 methyl ethylketone ketones water miscible 2.76 (27.5 g/100 mL) acetone watermiscible 2.77 butyrolactone lactones water miscible 4.12ester-caprolactone water miscible 3-4 dimethyl sulfoxide sulfoxideswater miscible 3.9 decylmethylsulfoxide 3.96

In one embodiment, the aprotic solvent is a solvent with a dipole momentof greater than about 2 D, or greater than about 2.2 D, or greater thanabout 2.4 D. In one embodiment, the aprotic solvent is a solvent with adipole moment of greater than about 2 D, or greater than about 2.2 D, orgreater than about 2.4 D and is water miscible. In another embodiment,the aprotic solvent is a solvent with a dipole moment of greater thanabout 2 D, or greater than about 2.2 D, or greater than about 2.4 D andis poorly miscible in water. In one embodiment, a solvent is misciblewith water if it forms a homogeneous solution with water in allproportions at room temperature (20-25° C.). A solvent is partiallymiscible if it forms a homogeneous solution with water in someproportions at room temperature (20-25° C.). A solvent is poorlymiscible if it does not form a homogeneous solution with water (20-25°C.).

The release of active agents from these polyorthoester and solventcompositions often demonstrates a biphasic behavior. There can be anearly phase release of active agent followed by a later phase release ofactive agent. In one embodiment, the release of the active agent in theearly phase can be controlled by the diffusion of the drug out of thecomposition while drug release in the later phase can be controlled bythe biodegradation of the polymer. The diffusional phase and theerosional phase of release of the active agent can be separated in timeor partially overlap or completely overlap.

In one embodiment, the solvent is selected to rapidly leave thecomposition. In this case, release of active agent at early time pointsis moderated by the presence and nature of the solvent in thecomposition and release of the active agent at later time points ismoderated by the nature of the polymer. In another embodiment, thesolvent is selected to slowly leave the composition. In this case,release of the active agent from the composition is moderated by boththe presence and nature of the solvent and the presence and nature ofthe polymer.

In another embodiment, the solvent may be selected in order to providedesired release kinetics of an active agent from the composition. Thesolvent may be selected to provide for a larger initial release of drug;for example, an initial drug release of about 25-40% in the first 2-5hours, and a slower release thereafter. Alternately, the solvent may beselected to provide a more zero order (linear) kinetic release profile;for example, a release of 10% of drug within 1-3 hours, and a slowcontinuous zero order release thereafter until the system is depleted ofdrug.

It has been found that the effect of the solvent on the release rate ofan active agent from the composition and the viscosity of thecomposition are generally independent. The viscosity of the compositioncan be adjusted by the addition of more solvent to reduce the viscosityand less solvent to increase the viscosity. The viscosity of thecomposition can also be modified by the selection of solvent. However,depending upon the nature of the solvent, these changes often have aminimal impact on the rate of release of an active agent. It has alsobeen recognized that the compositions and delivery systems providedherein surprisingly possess a greater stability over time with respectto the polyorthoester component, i.e., the degradability thereof, whencompared to compositions and delivery systems comprising a proticsolvent such as polyethylene glycol, such that the release profiles ofthe active agent are well maintained over time.

An “active agent” or “active ingredient” refers to any compound ormixture of compounds which produces a beneficial or useful result.Active agents are distinguishable from such components as vehicles,carriers, diluents, lubricants, binders and other formulating aids, andencapsulating or otherwise protective components. Examples of activeagents are pharmaceutical, agricultural or cosmetic agents. Suitablepharmaceutical agents include locally or systemically actingpharmaceutically active agents which may be administered to a subject bytopical or intralesional application (including, for example, applyingto abraded skin, lacerations, puncture wounds, etc., as well as intosurgical incisions) or by injection, such as subcutaneous, intradermal,intramuscular, intraocular or intra-articular injection. Suitablepharmaceutical agents include polysaccharides, DNA and otherpolynucleotides, antisense oligonucleotides, antigens, antibodies,vaccines, vitamins, enzymes, proteins, naturally occurring orbioengineered substances, and the like, anti-infectives (includingantibiotics, antivirals, fungicides, scabicides or pediculicides),antiseptics (e.g., benzalkonium chloride, benzethonium chloride,chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride,nitrofurazone, nitromersol and the like), steroids (e.g., estrogens,progestins, androgens, adrenocorticoids and the like), opioids (e.g.buprenorphine, butorphanol, dezocine, meptazinol, nalbuphine,oxymorphone and pentazocine), therapeutic polypeptides (e.g. insulin,erythropoietin, morphogenic proteins such as bone morphogenic protein,and the like), analgesics and anti-inflammatory agents (e.g., aspirin,ibuprofen, naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors andthe like), antipsychotic agents (for example, phenothiazines includingchlorpromazine, triflupromazine, mesoridazine, piperacetazine andthioridazine; thioxanthenes including chlorprothixene and the like),antiangiogenic agents (e.g., combresiatin, contortrostatin, anti-VEGFand the like), anti-anxiety agents (for example, benzodiazepinesincluding diazepam, alprazolam, clonazepam, oxazepam; and barbiturates),anti-depressants (including tricyclic antidepressants and monoamineoxidase inhibitors including imipramine, amitriptyline, doxepin,nortriptyline, amoxapine, tranylcypromine, phenelzine and the like),stimulants (for example, methylphenidate, doxapram, nikethamide and thelike), narcotics (for example, buprenorphine, morphine, meperidine,codeine and the like), analgesic-antipyretics and anti-inflammatoryagents (for example, aspirin, ibuprofen, naproxen and the like), localanesthetics (e.g., the amide- or anilide-type local anesthetics such asbupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine,lidocaine, tetracaine, ropivacaine, and the like), fertility controlagents, chemotherapeutic and anti-neoplastic agents (for example,mechlorethamine, cyclophosphamide, 5-fluorouracil, thioguanine,carmustine, lomustine, melphalan, chlorambucil, streptozocin,methotrexate, vincristine, bleomycin, vinblastine, vindesine,dactinomycin, daunorubicin, doxorubicin, tamoxifen and the like),cardiovascular and anti-hypertensive agents (for example, procainamide,amyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin,phentolamine, trimethaphan, captopril, enalapril and the like), drugsfor the therapy of pulmonary disorders, anti-epilepsy agents (forexample, phenytoin, ethotoin and the like), anti-hidrotics,keratoplastic agents, pigmentation agents or emollients, antiemeticagents (such as ondansetron, granisetron, tropisetron, metoclopramide,domperidone, scopolamine and the like). The composition of the presentapplication may also be applied to other locally acting active agents,such as astringents, antiperspirants, irritants, rubefacients,vesicants, sclerosing agents, caustics, escharotics, keratolytic agents,sunscreens and a variety of dermatologics including hypopigmenting andantipruritic agents. The term “active agents” further includes biocidessuch as fungicides, pesticides and herbicides, plant growth promoters orinhibitors, preservatives, disinfectants, air purifiers and nutrients.Pro-drugs and pharmaceutically acceptable salts of the active agents areincluded within the scope of the present application.

In one embodiment, the active agent is an antiemetic agent. Exemplaryamtiemetic agents include 5-HT₃ antagonists, dopamine antagonists,anticholinergic agents, GABA_(B) receptor agonists, NK₁ receptorantagonists, and GABA_(A)alpha₂ and/or alpha₃ receptor agonists. In oneembodiment the active agent is a 5-HT₃ antagonist selected from thegroup consisting of ondansetron, granisetron and tropisetron.

In another embodiment, the active agent is an anesthetic, e.g., an aminoamide anesthetic, where the composition is designed to comprise anaprotic solvent in an amount effective to provide a rate of release ofanesthetic effective for reducing or preventing pain. Representativeanesthetics include bupivacaine, levobupivacaine, dibucaine,mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. In oneparticular embodiment, the anesthetic is ropivacaine or bupivacaine.

In yet a further embodiment, the active agent is an opioid such asbuprenorphine.

The active agent or agents can be dissolved or dispersed into thecomposition comprising a polyorthoester and a biocompatible solvent. Theconcentration of the active agent in the composition may vary from about1 wt % to 20 wt %, 1 wt % to 10 wt %, 10 wt % to 20 wt %, 2 wt % to 5 wt%, 10 wt % to 15%, or 15 wt % to 20 wt % and may be 1 wt %, 1.1 wt %,1.2 wt %, 1.3 wt %, 1.4 wt %, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.8 wt %,1.9 wt %, 2 wt %, 2.1 wt %, 2.2 wt %, 2.3 wt %, 2.4 wt %, 2.5 wt %, 2.6wt %, 2.7 wt %, 2.8 wt %, 2.9 wt %, 3 wt %, 3.1 wt %, 3.2 wt %, 3.3 wt%, 3.4 wt %, 3.5 wt %, 3.6 wt %, 3.7 wt %, 3.8 wt %, 3.9 wt %, 4 wt %,4.1 wt %, 4.2 wt %, 4.3 wt %, 4.4 wt %, 4.5 wt %, 4.6 wt %, 4.7 wt %,4.8 wt %, 4.9 wt %, 5 wt %, 5 wt %, 5.1 wt %, 5.2 wt %, 5.3 wt %, 5.4 wt%, 5.5 wt %, 5.6 wt %, 5.7 wt %, 5.8 wt %, 5.9 wt %, 6 wt %, 6.1 wt %,6.2 wt %, 6.3 wt %, 6.4 wt %, 6.5 wt %, 6.6 wt %, 6.7 wt %, 6.8 wt %,6.9 wt %, 7 wt %, 7.1 wt %, 7.2 wt %, 7.3 wt %, 7.4 wt %, 7.5 wt %, 7.6wt %, 7.7 wt %, 7.8 wt %, 7.9 wt %, 8 wt %, 8.1 wt %, 8.2 wt %, 8.3 wt%, 8.4 wt %, 8.5 wt %, 8.6 wt %, 8.7 wt %, 8.8 wt %, 8.9 wt %, 9 wt %,9.1 wt %, 9.2 wt %, 9.3 wt %, 9.4 wt %, 9.5 wt %, 9.6 wt %, 9.7 wt %,9.8 wt %, 9.9 wt %, 10 wt %, 11 wt %, 11.1 wt %, 11.2 wt %, 11.3 wt %,11.4 wt %, 11.5 wt %, 11.6 wt %, 11.7 wt %, 11.8 wt %, 11.9 wt %, 12 wt%, 12.1 wt %, 12.2 wt %, 12.3 wt %, 12.4 wt %, 12.5 wt %, 12.6 wt %,12.7 wt %, 12.8 wt %, 12.9 wt %, 13 wt %, 13.1 wt %, 13.2 wt %, 13.3 wt%, 13.4 wt %, 13.5 wt %, 13.6 wt %, 13.7 wt %, 13.8 wt %, 13.9 wt %, 14wt %, 14.1 wt %, 14.2 wt %, 14.3 wt %, 14.4 wt %, 14.5 wt %, 14.6 wt %,14.7 wt %, 14.8 wt %, 14.9 wt %, 15 wt %, 15 wt %, 15.1 wt %, 15.2 wt %,15.3 wt %, 15.4 wt %, 5.5 wt %, 15.6 wt %, 15.7 wt %, 15.8 wt %, 15.9 wt%, 16 wt %, 16.1 wt %, 16.2 wt %, 16.3 wt %, 16.4 wt %, 16.5 wt %, 16.6wt %, 16.7 wt %, 16.8 wt %, 16.9 wt %, 17 wt %, 17.1 wt %, 17.2 wt %,17.3 wt %, 17.4 wt %, 17.5 wt %, 17.6 wt %, 17.7 wt %, 17.8 wt %, 17.9wt %, 18 wt %, 18.1 wt %, 18.2 wt %, 18.3 wt %, 18.4 wt %, 18.5 wt %,18.6 wt %, 18.7 wt %, 18.8 wt %, 18.9 wt %, 19 wt %, 19.1 wt %, 19.2 wt%, 19.3 wt %, 19.4 wt %, 19.5 wt %, 19.6 wt %, 19.7 wt %, 19.8 wt %,19.9 wt %, 20 wt %.

The compositions may comprise a second active agent. In one embodiment,a first and second antiemetic agent is included in the composition. Inone variation, the second antiemetic agent is selected from the groupconsisting of alpha-2 adrenoreceptor agonists, a dopamine antagonist, ananticholinergic agent, a GABA_(B) receptor agonist, an NK₁ receptorantagonist, and a GABA_(A)alpha₂ and/or alpha₃ receptor agonist. Inanother variation, the alpha-2 adrenoreceptor agonists is selected fromthe group consisting of clonidine, apraclonidine, para-aminoclonidine,brimonidine, naphazoline, oxymetazoline, tetrahydrozoline, tramazoline,detomidine, medetomidine, dexmedetomidine, B-HT 920, B-HIT 933,xylazine, rilmenidine, guanabenz, guanfacine, labetalol, phenylephrine,mephentermine, metaraminol, methoxamine and xylazine.

In another aspect, the compositions and systems described herein are fortreatment of a subject, and the composition or system is administeredvia injection to a subject in need.

In one embodiment, the compositions are for use in a method for thetreatment of emesis induced by a chemotherapeutic agent, byradiation-induced nausea and vomiting, and/or by post-operative inducednausea and vomiting in a patient. The treatment includes administeringto the patient a composition comprising an anti-emetic, such as a 5-HT₃antagonist, where the composition is designed to include an aproticsolvent that yields a rate of release for effective anti-emetic therapy.

In another embodiment, the compositions are for use in a method ofproviding local anesthesia to a patient in need. The treatment includesadministering to a patient a composition comprising an anesthetic, e.g.,an amino amide anesthetic such as ropivacaine or bupivacaine, where thecomposition is designed to comprise an aprotic solvent in an amounteffective to provide a rate of release of anesthetic effective forreducing or preventing pain. Local administration can be, e.g., at anerve, into the epidural space, intrathecal, or directly to a surgicalsite or wound.

One further embodiment also provides a method of providing regionalaesthesia to a subject by administering a composition comprising ananesthetic, e.g., an amino amide anesthetic such as ropivacaine orbupivacaine, in a region of tissue near a nerve to provide a local orregional nerve block. The dosages can be administered either as a nerveblock (including acting as a motor block), or as a sensory block.

In yet another embodiment, the compositions and delivery systemsprovided herein are for reducing or treating acute or chronic pain. Thetreatment includes administering to a patient a composition comprisingan opioid, such as buprenorphine or another opioid, where thecomposition is designed to comprise an aprotic solvent in an amounteffective to provide a rate of release of the opioid effective forreducing or preventing pain.

More generally, the compositions and systems are administered to asubject (e.g., patient) in need of a treatment or prevention of acondition, in an effective amount of the flowable composition describedherein. The compositions provide the advantages of liquid application toform medical or surgical devices and/or delivery systems for activeagents (e.g., drugs). The present liquid polymer/solvent compositionsalso allow the use of smaller gauge needles compared to other liquidpolymer systems made without a solvent. The solvents used in the presentcompositions allow an active agent to also be administered as a solutionin contrast to liquid polymer systems made without solvents. The use ofliquid biodegradable polymers in the present system also allows the rateof release of an active agent and degradation of the flowablecomposition to be varied over a wide range in contrast to thenon-polymeric flowable compositions.

An in vivo study was conducted to evaluate release of an active agentfrom a delivery system comprised of a polyorthoester and an aproticsolvent, using DMSO as the exemplary solvent. Example 6 describes thedelivery system and the protocol. Plasma samples were taken from eachdog in the study 24 hours before administration of a delivery system,and after administration at the following time points: 1, 6, 12, 24, 48,72, 96, 120, 144, and 168 hours. The treatment was repeated 2 weekslater with a slightly different delivery system, and plasma samples wereagain taken. The plasma concentration of the active agent in thedelivery systems, granisetron, as a function of time, in hours, is shownin FIG. 5 . Both formulations provided measurable plasma concentrationsof granisetron for at least 5 days. The formulation with the higheramount (34.3%) of DMSO gave a higher Cmax than did the formulation withthe lower amount (26.5 wt %) DMSO.

Additional in vivo studies were conducted to further evaluate therelease of additional exemplary active agents from delivery systemscomprised of a polyorthoester and an aprotic solvent, using N-methylpyrrolidone and dimethyl acetamide as the exemplary solvents. Details ofthe studies are provided in Examples 9 and 12, respectively. Inconsidering the study described in Example 9, the following compositionswere administered: Formulation No. 07-03 comprised 75.0 wt %polyorthoester, ropivacaine (4.75 wt % free base, 0.25 wt % HCl salt),and 25.0 wt % N-methyl-2-pyrrolidone (NMP); Formulation No. 07-04comprised 56.4 wt % polyorthoester, 20.70 wt % ropivacaine free base,22.9 wt % dimethyl acetamide (DMAc); Formulation No. 07-05 comprised45.0 wt % polyorthoester, 10.00 wt % ropivacaine free base, and 45.0 wt% N-methyl-2-pyrrolidone; and Formulation No. 07-06 comprised 71.0 wt %polyorthoester, ropivacaine (4.50 wt % free base, 0.50 wt % HCl salt),and 24.0 wt % N-methyl-2-pyrrolidone. Plasma samples were taken fromeach dog in the study 24 hours prior to administration, and afteradministration at the following time points: 1, 6, 12, 24, 48, 72, 96,120, 144, and 168 hours. The plasma concentration of the active agent inthe delivery systems, ropicavaine, as a function of time, in hours, isshown in FIG. 6 . Advantageously, all formulations provided measurableplasma concentrations of ropivacaine for at least 5 days. The deliverysystems administered contained from 45-75 wt % polyorthoester, fromabout 5-21 wt % ropivacaine (including both free base and acid saltforms), and from about 23-45 wt % aprotic solvent. In some instances, asmall amount of a salt form of the active agent such as thehydrochloride salt, was included in the formulation to aid indissolution. Interestingly, the formulations with the lowest weightpercentage of ropivacaine, Formulations 07-03 (5 wt % total) and 07-06(5 wt % total), exhibited higher Cmax values than did the formulationscontaining greater amounts of drug (10 wt % and 20 wt %). Bothformulations 07-03 and 07-06 contained similar amounts of the aproticsolvent, NMP (25 wt % and 24 wt % respectively). This example furtherdemonstrates the utility of delivery systems as described generallyherein, to provide release into the bloodstream of an active agent overan extended period of time post administration.

A similar in vivo study is described in detail in Example 12, where theactive agent comprised in the delivery systems was bupivacaine and theexemplary solvent was NMP. Two different formulations were administeredas follows: 55.0 wt % polyorthoester, 15.0 wt % bupivacaine, and 30.0 wt% N-methyl-2-pyrrolidone (NMP) (Formulation 02-01); and 42.5 wt %polyorthoester, 15.0 wt % bupivacaine, and 42.5 wt %N-methyl-2-pyrrolidone (Formulation 02-02). Both formulations comprisedthe same weight percentage of drug, bupivacaine. A graph of plasmaconcentration of bupivacaine, in ng/mL, in dogs, as a function of time,in hours, is provided as FIG. 7 . As can be seen, both formulations wereeffective to provide measurable plasma concentrations of bupivacaine forat least 5 days post-administration. Both formulations possessed similarCmax values, however, the formulation containing a higher amount of NMP(42.5 wt %) was effective to maintain higher plasma concentrations ofdrug over the time period from about 4 days to about 7 dayspost-administration when compared to the formulation containing thelower amount of NMP (30 wt %).

A study was also conducted to examine the pharmacodynamics of localanesthetic formulations administered in vivo. Thus, in a furtherembodiment, formulations as provided herein are useful in reducing pain,e.g., in reducing post-surgical incisional pain in a patient. Turningback to the study carried out, as described in Example 13, twopolyorthoester-aprotic solvent-anesthetic formulations were evaluatedfor their ability to reduce post-surgical incisional pain in a modelsystem, i.e., a porcine model. The formulations administered locallycomprised (i) 30.0 wt % NMP, 55.0 wt % polyorthoester of formula III,and 15 wt % bupivacaine; and (ii) 24.0 wt % NMP, 72.0 wt %polyorthoester, and 5.00 wt % ropivacaine. Administration was either bydirect instillation or by injection into the tissue surrounding thewound. Activity of the anesthetic was evaluated by assessment ofreduction of post-operative pain. Direct instillation of bothformulations generally resulted in a greater degree of pain reduction incomparison to the injected formulations, with efficacy indicated up toat least six days post-administration. While the instilled samples wereeffective in reducing/eliminating pain shortly after administration,e.g., at the 1 hour time point, the injected samples were generally mosteffective in reducing pain at about 3-5 hours post-administration. Allformulations, regardless of mode of administration, and for bothanesthetics, were effective to reduce pain for up to at least 6 dayspost administration, and beyond. Thus, compositions such as providedherein are effective in providing extended pain relief, among otheruses.

III. Aspects and Embodiments

Aspects and embodiments of the delivery systems, compositions, andrelated methods as provided herein are set forth below.

In a first aspect, provided herein is a delivery system, comprising:

a polyorthoester; an aprotic solvent in which the polyorthoester ismiscible to form a single phase; and a therapeutically active agentdispersed or solubilized in the single phase; wherein the active agentis released from the system over a period of between approximately 1 dayand approximately 8 weeks.

In a second aspect, provided is a flowable composition, comprising: apolyorthoester; a solvent in which the polyorthoester is miscible toform a single phase; and a therapeutically active agent dispersed orsolubilized in the single phase; wherein the solvent is an aproticsolvent with a dipole moment greater than about 2 Debye (D).

In a third aspect, provided herein is a method of treatment, comprisingdispensing from a needle a composition comprised of a polyorthoester, anaprotic solvent in which the polyorthoester is miscible to form a singlephase; and a therapeutically active agent dispersed or solubilized inthe single phase, wherein the solvent is selected to achieve acontrolled release of the active agent from the composition according toa predetermined release profile, and wherein the release of the activeagent is for a period of between approximately 1 day and approximately 8weeks.

In a first embodiment related to the delivery system of the first aspector the flowable composition of the second aspect or the composition ofthe third aspect, the delivery system or flowable composition orcomposition has a viscosity of less than about 10,000 cP at 37° C.

In a second embodiment related to the first, second or third aspectsabove, the aprotic solvent is an organic solvent having a watersolubility of greater than 25% by weight of the solvent in water at roomtemperature.

In a third embodiment related to the first, second or third aspectsabove, the aprotic solvent is a dipolar aprotic solvent.

In a fourth embodiment related to the first, second or third aspectsabove, the aprotic solvent is in a class selected from the groupconsisting of an amide, a biocompatible oil, an ester of an acid, anester of an alcohol, an ether, a ketone, a sulfoxide, a triglyceride,and an ester of a triglyceride.

In a fifth embodiment related to the first, second or third aspectsabove, the aprotic solvent is an amide. In yet a further embodiment ofthe foregoing, the solvent is an amide selected from the groupconsisting of 2-pyrrolidone, dimethyl formamide, n-methyl-2-pyrrolidone,n-ethyl-2-pyrrolidone, dimethyl acetamide, n-cyclohexyl-2-pyrrolidoneand caprolactam. In yet a further embodiment, the solvent is1-dodecylazacycloheptan-2-one (azone).

In a sixth embodiment related to the first, second or third aspectsabove, the aprotic solvent is a biocompatible oil. In a furtherembodiment related to the foregoing, the solvent is a biocompatible oil,excluding non-hydrogenated vegetable oils, partially-hydrogenatedvegetable oils, peanut oil, sesame oil or sunflower oil.

In a 7^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is an ester of an acid. In a furtherembodiment related to the foregoing, the solvent is an ester of an acidselected from the group consisting of carboxylic acid esters and fattyacid esters, excluding propylene glycol dicaprate and propylene glycoldicaprylate. In yet a further embodiment related to the 7^(th)embodiment, the solvent is selected from the group consisting of ethylacetate, benzyl benzoate, methyl acetate, isopropyl myristate, ethyloleate, methyl lactate and ethyl lactate.

In an 8^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is an ester of an alcohol. In an embodimentrelated to the foregoing, the solvent is propylene carbonate(4-methyl-1,3-diololan-2-one).

In a 9^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is an ether. In an embodiment related to theforeoing, the ether is selected from dimethyl isosorbide andtetrahydrofuran.

In a 10^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is a ketone. In yet a further embodimentrelated to the foregoing, the solvent is a ketone selected from thegroup consisting of acetone and methyl ethyl ketone. In yet anotherembodiment related to the 10^(th) embodiment, the solvent is a lactoneselected from caprolactone and butyrolactone.

In an 11^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is a sulfoxide. In a further embodimentrelated to the foregoing, the solvent is a sulfoxide selected from thegroup consisting of dimethyl sulfoxide and decylmethylsulfoxide. In a12^(th) embodiment related to the first, second or third aspects above,the aprotic solvent is a triglyceride or an ester of a triglyceride.

In a 13^(th) embodiment related to the first, second or third aspectsabove, the solvent is not propylene glycol dicaprate, propylene glycoldicaprylate, glycofurol, a non- or partially-hydrogenated vegetable oil,glyceryl caprylate, glyceryl captate, glyceryl caprylate/caprate,glyceryl 10 caprylate/caprate/laurate, poly(ethyleneglycol-copolypropylene glycol, poly(ethylene glycol)monomethyl ether550, poly(ethylene glycol)dimethyl ether 250, glycerine triacetate, or atriglyceride.

In a 14^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is 2-pyrrolidone.

In a 15^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is dimethylformamide.

In a 16^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is N-methyl-2-pyrrolidone.

In a 17^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is N-ethyl-2-pyrrolidone.

In an 18^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is dimethylacetamide.

In a 19^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is N-cyclohexyl-2-pyrrolidone.

In a 20^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is caprolactam.

In a 21^(st) embodiment related to the first, second or third aspectsabove, the aprotic solvent is 1-dodecylazacycloheptan-2-one (azone).

In a 22^(nd) embodiment related to the first, second or third aspectsabove, the aprotic solvent is ethyl acetate.

In a 23^(rd) embodiment related to the first, second or third aspectsabove, the aprotic solvent is benzyl benzoate.

In a 24^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is methyl acetate.

In a 25^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is isopropyl myristate.

In a 26^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is ethyl oleate.

In a 27^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is methyl lactate.

In a 28^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is ethyl lactate.

In a 29^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is propylene carbonate(4-methyl-1,3-diololan-2-one).

In a 30^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is dimethyl ether.

In a 31^(st) embodiment related to the first, second or third aspectsabove, the aprotic solvent is dimethyl isosorbide.

In a 32^(nd) embodiment related to the first, second or third aspectsabove, the aprotic solvent is tetrahydrofuran.

In a 33^(rd) embodiment related to the first, second or third aspectsabove, the aprotic solvent is acetone.

In a 34^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is methyl ethyl ketone.

In a 35^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is aprolactone.

In a 36^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is butyrolactone.

In a 37^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is dimethyl sulfoxide.

In a 38^(th) embodiment related to the first, second or third aspectsabove, the aprotic solvent is decylmethylsulfoxide.

In a 39^(th) embodiment related to the first, second or third aspectsabove, and any one of embodiments 1-38, the aprotic solvent is presentin an amount ranging from about 10 percent to about 70 percent byweight, relative to the total weight of the composition.

In a 40^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 20 percent to about 50percent by weight.

In a 41^(st) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 10-60 wt %.

In a 42^(nd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 15-60 wt %.

In a 43^(rd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 15-50 wt %.

In a 44^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 20-60 wt %.

In a 45^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 25-50 wt %.

In a 46^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 30-70 wt %.

In a 47^(th(i)) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 30-60 wt %.

In a 47^(th(ii)) embodiment related to the first, second or thirdaspects above, or any one of embodiments 1-38, the aprotic solvent ispresent in the composition in an amount ranging from about 10-20 wt %.

In a 48^(th(i)) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 30-50 wt %.

In a 48^(th(ii)) embodiment related to the first, second or thirdaspects above, or any one of embodiments 1-38, the aprotic solvent ispresent in the composition in an amount ranging from about 15-25 wt %.

In a 49^(th(i)) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 35-70 wt %.

In a 49^(th(ii)) embodiment related to the first, second or thirdaspects above, or any one of embodiments 1-38, the aprotic solvent ispresent in the composition in an amount ranging from about 20-30 wt %.

In a 50^(th(i)) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 35-60 wt %.

In a 50^(th(ii)) embodiment related to the first, second or thirdaspects above, or any one of embodiments 1-38, the aprotic solvent ispresent in the composition in an amount ranging from about 15-35 wt %.

In a 51^(st(i)) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-38, the aprotic solvent is present inthe composition in an amount ranging from about 35-50 wt %.

In a 51^(st(ii)) embodiment related to the first, second or thirdaspects above, or any one of embodiments 1-38, the aprotic solvent ispresent in the composition in an amount ranging from about 20-35 wt %.

In a 51^(st(iii)) embodiment related to the first, second or thirdaspects above, or any one of embodiments 1-38, the aprotic solvent ispresent in the composition in an amount ranging from about 20-40 wt %.

In a 52^(nd) embodiment related to the first, second or third aspectsabove, and any one of embodiments 1-51, the polyorthoester has astructure defined by formula I, formula II, formula III or formula IV:

where:

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5; R*is a C₁₋₄ alkyl; R^(o), R″ and R′″ are each independently H or C₁₋₄alkyl; n is an integer of at least 5; and A is a diol.

In a 53^(rd) embodiment related to the first, second or third aspectsabove, and any one of embodiments 1-51, the polyorthoester has astructure of formula III where R is a bond, —(CH₂)_(a)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 10, and b and care independently integers of 1 to 5; R* is a C₁₋₄ alkyl; R^(o), R″ andR′″ are each independently H or C₁₋₄ alkyl; n is an integer of at least5; and A is R¹, R², R³, or R⁴, where R¹ is:

where p and q are integers that vary from between about 1 to 20 and theaverage number of p or the average of the sum of p and q is between 1and 7 in an least a portion of the monomeric units of the polymer; R⁵ ishydrogen or C₁₋₄ alkyl; and

R⁶ is:

where s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷ ishydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where x is an integer of 0 to 100; y is an integer of 2 to 200; R⁸ ishydrogen or C₁₋₄ alkyl; R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene; R¹¹is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹² togetherare C₃₋₁₀ alkylene; and R⁴ is the residue of a diol containing at leastone functional group independently selected from amide, imide, urea, andurethane groups.

In a 54^(th) embodiment related to the first, second or third aspectsabove, and any one of embodiments 1-51, the polyorthoester has astructure according to formula III where A is R¹, R³, or R⁴, where R¹is:

where p and q are integers that vary from between about 1 to 20 and theaverage number of p or the average of the sum of p and q is between 1and 7 in an least a portion of the monomeric units of the polymer; R³and R⁶ are each independently:

where x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁₋₄ alkyl; R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene; R¹¹is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹² togetherare C₃₋₁₀ alkylene; R⁴ is a residual of a diol containing at least onefunctional group independently selected from amide, imide, urea andurethane groups; and R⁵ is hydrogen or C₁₋₄ alkyl.

In a 55^(th) embodiment related to the first, second or third aspectsabove, and any one of embodiments 1-53, the polyorthoester has amolecular weight between 3,000 and 10,000.

In a 56^(th(i)) embodiment related to embodiments 52-54, the fraction ofthe A units that are of the formula R¹ is between 0 and 25 mole percent.In a 56^(th(ii)) embodiment related to embodiments 52-54, the fractionof the A units that are of the formula R¹ is between 0 and 10 molepercent. In a 56^(th(iii)) embodiment related to embodiments 52-54, thefraction of the A units that are of the formula R¹ is between 0 and 5mole percent. In a 56^(th(iv)) embodiment related to embodiments 52-54,the fraction of the A units that are of the formula R¹ is between 10 and25 mole percent.

In a 57^(th) embodiment related to embodiments 52-54, the polyorthoesteris of formula III, where none of the units have A equal to R²; R³ is:

where x is an integer of 0 to 10; y is an integer of 2 to 30; and R⁶ is:

where s is an integer of 0 to 10; t is an integer of 2 to 30; and R⁵,R⁷, and R⁸ are independently hydrogen or methyl. In yet anotherembodiment related to embodiment 57, R³ and R⁶ are both—(CH₂—CH₂—O)₂—(CH₂—CH₂)—; R⁵ is methyl; and p is 1 or 2.

In a 58^(th) embodiment related to the first, second or third aspectsabove, and any one of embodiments 1-51, the polyorthoester is selectedfrom formulas III and IV below:

where R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)O(CH₂)_(c)—; where a is aninteger from 1 to 10, and b and c are independently integers from 1-5;R* is a C1-4 alkyl; R0, RII and RIII are each independently H or C₁₋₄alkyl; n is an integer of at least 5, for example, from 5 to 1000; andA is R¹, R², R³, or R⁴, where R¹ is

where: p is an integer of 1 to 20; R⁵ is hydrogen or C1-4 alkyl; and

R⁶ is:

where:s is an integer of 0 to 30; t is an integer of 2 to 200; andR⁷ is hydrogen or C1-4 alkyl;

R² is:

R³ is:

where:x is an integer of 0 to 100; y is an integer of 2 to 200;q is an integer of 2 to 20; r is an integer of 1 to 20; R⁸ is hydrogenor C1-4 alkyl;R⁹ and R¹⁰ are independently C1-12 alkylene; R¹¹ is hydrogen or C1-6alkyl and R¹² is C1-6 alkyl; or R¹¹ and R¹² together are C3-10 alkylene;andR⁴ is the residue of a diol containing at least one functional groupindependently selected form amide, imide, urea, and urethane groups;in which at least 0.01 mol percent of the A units are of the formula R¹.In a sub-embodiment of the 58^(th) embodiment above, none of the A unitsare of formula R¹.

In a 59^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-58, the amount of polyorthoesterranges from about 30 percent to about 90 percent by weight relative tothe overall composition or delivery system.

In a 60^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-58, the amount of polyorthoesterranges from about 50 percent to about 80 percent by weight relative tothe overall composition or delivery system.

In a 61^(st) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the active agent is dissolved inthe composition or delivery system.

In a 62^(nd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the active agent is dispersed inthe composition or delivery system.

In a 63^(rd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system ranges from about 1 wt % to 20 wt %.

In a 64^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system ranges from about 10 wt % to 20 wt %.

In a 65^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system ranges from about 2 wt % to 5 wt %.

In a 66^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system ranges from about 10 wt % to 15 wt %.

In a 67^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system ranges from about 15 wt % to 20 wt %.

In a 68^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 1 wt %.

In a 69^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 2 wt %.

In a 70^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 3 wt %.

In a 71^(st) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 4 wt %.

In a 72^(nd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 5 wt %.

In a 73^(rd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 6 wt %.

In a 74^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 7 wt %.

In a 75^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 8 wt %.

In a 76^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 9 wt %.

In a 77^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 10 wt %.

In a 78^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 11 wt %.

In a 79^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 12 wt %.

In a 80^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 13 wt %.

In a 81^(st) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 14 wt %.

In a 82^(nd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 15 wt %.

In a 83^(rd) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 16 wt %.

In a 84^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 17 wt %.

In a 85^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 18 wt %.

In a 86^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 19 wt %.

In a 87^(th) embodiment related to the first, second or third aspectsabove, or any one of embodiments 1-60, the amount active agent in thecomposition or delivery system is about 20 wt %.

In an 88^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is granisetron.

In an 89^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is a local “caine”-type anesthetic.

In a 90^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is selected from bupivacaine, levobupivacaine,dibucaine, mepivacaine, procaine, lidocaine, tetracaine, andropivacaine.

In a 91^(st) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is bupivacaine.

In an 92^(nd) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is ropivacaine.

In an 93^(rd) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is levobupivacaine.

In an 94^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is dibucaine.

In an 95^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is mepivacaine.

In an 96^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is procaine.

In an 97^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is lidocaine.

In an 98^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is tetracaine.

In an 99^(th) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionor delivery system is an anti-emetic.

In a 100^(th) embodiment related to the first, second or third aspectsabove, the polyorthoester is represented by the structure shown asFormula III, the active agent is granisetron in an amount between 1-5percent by weight, and the aprotic solvent is DMSO in an amount between10-35 percent by weight.

In an 101^(st) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-100, the composition or delivery systemhas a viscosity of less than about 10,000 cP at 37° C.

In a 102^(nd) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionis an opioid.

In a 103^(rd) embodiment related to the first, second or third aspectsabove, or any of embodiments 1-87, the active agent in the compositionis bupenorphine.

In a fourth aspect, provided is method of administering atherapeutically active agent comprising dispensing from a needle adelivery system or a composition related to the first or second oraspects above, or any one of embodiments 1-103.

IV. EXAMPLES

The following examples are illustrative in nature and are in no wayintended to be limiting.

Example 1 Delivery Systems Comprising an Aprotic Solvent

Compositions, 2 to 5 grams of each, of a polyorthoester of formula IIIwith triethylene glycol and R¹ in a 2:1 ratio, granisetron base andvarying amounts of DMSO or DMAC were prepared by dissolving theappropriate amount of granisetron base into each solvent atapproximately 80° C.

The drug solutions were then mixed with the appropriate amount ofpolymer at an elevated temperature, until homogenous, to formcompositions with 20% (DMAC only), 30%, 40%, and 50% solvent and 2%granisetron base. The release of solvent from each composition wasdetermined by placing a small amount of each polymer formulation(approximately 50 mg) into 15-20 mL of phosphate buffered saline inglass scintillation vials. The samples were then incubated at 37° C.without agitation. At 24 hour intervals the vials were inverted severaltimes and aliquots of the buffer solution were removed and analyzed foreach solvent by gas chromatography. The results are shown in FIGS. 1A-1Band in the tables below.

TABLE 1-1 In Vitro Release of DMSO Percent Solvent Released forCompositions Time with Indicated Amount of DMSO (hours) 30% DMSO 40%DMSO 50% DMSO 0   0%   0%   0% 24 30.1% 43.5% 58.5% 48 40.9% 57.0% 71.7%72 73.1% 70.0% 83.7% 96 87.0% 87.1% 93.0% 168 90.4% 94.9% 94.3%

TABLE 1-2 In Vitro Release of DMAC Percent Solvent Released forCompositions Time with Indicated Amount of DMAC (hours) 20% DMAC 30%DMAC 40% DMAC 50% DMAC 0   0%    0%   0%    0% 24 78.9%  92.1% 90.0%112.4% 48 82.1% 105.6% 88.1% 101.0% 72 98.8% 100.3% 97.1%  98.7% 9697.3%  97.7% 95.7%  96.3% 168 107.3%  109.2% 107.0%  107.0%

Example 2 Measurement of Viscosity

Compositions, 2 to 5 grams of each, of a polyorthoester (POE) of formulaIII, granisetron base and varying amounts of dimethyl sulfoxide orN-methyl pyrrolidone were prepared by dissolving the appropriate amountof granisetron base into each solvent at approximately 80° C. The drugsolutions were then mixed with the appropriate amount of polymer at anelevated temperature, until homogenous, to form compositions with 10%,20%, and 30% solvent and 2% granisetron base. Viscosity of thecompositions was measured using a Brookfield cone and plate viscometer.The viscosity measurements are performed at 37° C.

TABLE 2-1 Viscosity of Compositions Viscosity in Viscosity in DMSO (cP)NMP (cP) 90% POE/10% Solvent 199,630 117,663 80% POE/20% Solvent 14,1629966 70% POE/30% Solvent 2608 1633

Example 3 Drug Release Modulated by Selection of Aprotic Solvent

Compositions, 2 to 5 grams of each, of a polyorthoester of Formula III,granisetron, and varying amounts of DMSO or DMAC were prepareddissolving the appropriate amount of granisetron base into each solventat approximately 80° C. The drug solutions were then mixed with theappropriate amount of polymer at an elevated temperature, untilhomogenous, to form compositions with 20% (DMAC only), 30%, 40%, and 50%solvent and 2% granisetron base. The release of solvent from eachcomposition was determined by placing a small amount of each polymerformulation (approximately 50 mg) into 15-20 mL of phosphate bufferedsaline in glass scintillation vials. The samples were then incubated at37° C. without agitation. At 24 hour intervals the vials were invertedseveral times and aliquots of the buffer solution were removed andanalyzed for granisetron by high performance liquid chromatography. Theresults are shown in FIGS. 2A-2B and in the tables below.

TABLE 3-1 In Vitro Release of Granisetron from Composition with DMSOTime Granisetron Release (%) (hrs) 30% DMSO 40% DMSO 50% DMSO 0   0%  0%   0% 24 28.2% 44.8% 62.0% 48 36.9% 52.9% 71.3% 72 66.2% 64.2% 84.0%96 73.9% 71.2% 93.1% 168 96.1% 100.7%  101.5% 

TABLE 3-2 In Vitro Release of Granisetron from Composition with DMACTime Granisetron Release (%) (hrs) 20% DMAC 30% DMAC 40% DMAC 50% DMAC 0  0%    0%   0%   0% 24 30.9%  41.0% 40.4% 71.3% 48 47.3% 100.0% 51.1%80.8% 72 98.4% 103.6% 81.2% 94.8% 96 110.2%  115.0% 90.5% 104.9%  168106.9%  106.5% 101.4%  103.9% 

Example 4 Delivery Systems Comprising an Aprotic Ether Solvent

Compositions of a polyorthoester of formula III, granisetron base andtwo concentrations of dimethyl isosorbide were prepared by firstdissolving the appropriate amount of granisetron base into dimethylisosorbide at elevated temperature. The drug solution was then mixedwith the appropriate amount of polymer at an elevated temperature, untilhomogenous, to form compositions with 19.6% and 9.8% dimethyl isosorbideand 2% granisetron base. The release of drug from each composition wasdetermined by placing a small amount of each polymer formulation(approximately 50 mg) into 15-20 mL of phosphate buffered saline inglass scintillation vials. The samples were then incubated at 37° C.without agitation. At 24 hour intervals the vials were inverted severaltimes and aliquots of the buffer solution were removed and analyzed forgranisetron by high performance liquid chromatography. The results areshown in FIG. 4 and in the Table 4-1 below.

TABLE 4-1 In Vitro Release of Granisetron Time 19.6% Dimethyl 9.8%Dimethyl (hrs) isosorbide isosorbide 2  4%  4% 4  7%  6% 6 10%  9% 2427% 27% 48 36% 37% 72 60% 45% 96 84% 73% 168 88% 110%  192 88% 110%  21688% 111%  240 89% 111%  264 89% 111% 

Example 5 Delivery Systems Comprising an Aprotic Solvent

Compositions comprised of a polyorthoester of Formula III and thefollowing drugs and solvents are prepared: meloxicam, granisetron,mepivacaine, bupivacaine, ropivacaine, and buprenorphine and DMSO, NMP,DMAC and dimethyl isosorbide. Release of drug and solvent from thecompositions is measured in an in vitro dissolution apparatus. Rate ofdrug release correlates with rate of solvent release for DMSO and NMP.Compositions with DMAC provide a rate of drug release that depends onthe solubility of the drug in the solvent.

Example 6 Pharmacokinetic Analysis of Granisetron Formulations inCanines

Ten dogs were treated with a formulation containing, 2% granisetron basein 63.7% polyorthoester of Formula III—34.3% DMSO (5 male—5 female) onday 1 of week 1. Each dog received the entire contents of 1 syringecontaining 0.5 grams formulation (10 mg granisetron). Plasma sampleswere taken from each dog at the following time points: −24, 1, 6, 12,24, 48, 72, 96, 120, 144, and 168 hours and frozen. On day 1 of week 3,the study was repeated in the same 10 dogs. For this second portion ofthe study, the ten dogs were treated with a formulation containing, 2%granisetron base in 71.5% polyorthoester of Formula III—26.5% DMSO (5male, 5 female). Again, plasma samples were taken from each dog at thefollowing time points: −24, 1, 6, 12, 24, 48, 72, 96, 120, 144, and 168hours and frozen. The plasma samples were subsequently analyzed byLC/MS/MS for granisetron. A plot of the plasma concentration ofgranisetron versus time is presented in FIG. 5 . Both formulationsprovided measurable plasma concentrations of granisetron for at least 5days. The formulation with the higher amount of DMSO gave a higher Cmaxthan did the formulation with 26.5% DMSO.

Example 7 Ropivacaine Delivery Systems Comprising an Aprotic Solvent

Compositions containing between 45% to 80% polyorthoester of formulaIII, between 20% and 45% of an aprotic solvent, and between 4% and 22.0%ropivaciane were prepared. Ropivacaine used in these compositionsoptionally contained a combination of ropivacaine base and ropivacainehydrochloride. For compositions where the ropivacaine was in solution,the composition was prepared by first the dissolving the appropriateamount of ropivacaine base into the appropriate amount of aproticsolvent at approximately 80° C. The drug solution was then mixed withthe appropriate amount of polymer at an elevated temperature, untilhomogenous. For compositions where the ropivacaine was in suspension,the composition was prepared by first combining the appropriate amountof polyorthoester polymer and the appropriate amount of aprotic solventat approximately 80° C. The solution was cooled to approximately roomtemperature and the ropivacaine was added to the polymer solventmixture. Exemplary compositions are presented in Table 7-1.

TABLE 7-1 Ropivacaine Delivery Systems: Polyorthoester-Aprotic SolventCompositions Ropivacaine Formulation Solvent Ropivacaine RopivacaineComposition ID ID Base % HCl Salt % % POE % Solvent Form 07-01 DMAc22.00% 0.00% 53.7% 24.2% Suspension 07-02 NMP  9.10% 0.50% 45.2% 45.2%Dissolved 07-03 NMP  4.75% 0.25% 72.0% 24.0% Dissolved 07-04 DMAc 20.70%0.00% 56.4% 22.9% Suspension 07-05 NMP 10.00% 0.00% 45.0% 45.0%Dissolved 07-06 NMP  4.50% 0.50% 71.0% 24.0% Dissolved 07-08 NMP  4.75%0.25% 66.5% 28.5% Dissolved 07-09 NMP  4.00% 1.00% 80.0% 20.0% Dissolved07-10 NMP  3.50% 1.50% 80.0% 20.0% Dissolved 07-11 DMSO  3.96% 0.24%68.5%  4.7% Dissolved NMP DMSO 22.5% NMP 07-12 NMP  3.80% .020% 72.0%24.0% Dissolved 07-13 DMSO  9.00% 0.00% 49.7% 41.3% Dissolved 07-14 DMSO 4.15% 0.85% 52.0% 43.0% Dissolved 07-15 NMP  3.60% 0.40% 67.1% 28.9%Dissolved 07-16 NMP  9.0%  1.0% 65.0% 25.0% Suspension 07-17 NMP  7.5% 2.5% 65.0% 25.0% Suspension 07-18 NMP  5.0%  5.0% 65.0% 25.0%Suspension 07-19 DMAc  9.0%  1.1% 71.9% 17.9% Suspension 07-20 DMAc 7.4%  2.6% 72.0% 18.0% Suspension 07-21 DMAc  5.0%  5.0% 72.0% 18.0%Suspension

Example 8 In-Vitro Release of Ropivacaine Compositions

The release of ropivacaine from the composition was determined byplacing a small amount of the polymer formulation (approximately 50 mg)into 150 mL of phosphate buffered saline. The samples were thenincubated at 37° C. without agitation. At 24 hour intervals, 1 mLsamples were taken from the vials without any agitation of the solution.Each sample was analyzed by HPLC to determine the concentration ofropivacaine. The cumulative drug release from the 50 mg depot was thencalculated.

TABLE 8-1 in Vitro Release of Ropivacaine Percent Ropivacaine Releasedfor Compositions Composition # 24 hrs 48 hrs 72 hrs 96 hrs 120 hrs 144hrs 168 hrs 192 hrs 216 hrs 07-02 35.78 72.20 83.30 86.60 91.44 95.45N/S N/S N/S 07-03 45.26 51.67 52.54 58.65 67.06 69.99 N/S N/S N/S 07-0425.09 34.35 37.08 45.69 55.92 63.29 N/S N/S N/S 07-06 26.55 43.97 57.0171.73 N/S N/S 93.96 97.35 07-08 29.28 50.98 63.79 79.06 112.86  121.67 N/S N/S N/S 07-11  8.61 18.02 25.49 34.17 N/S N/S 59.53 81.58 N/S 07-1310.03 29.17 39.27 58.08 67.97 77.05 N/S N/S N/S 07-14 20.66 45.77 48.4861.73 76.75 80.08 N/S N/S N/S 07-15 31.80 40.73 50.54 54.33 N/S N/S N/S85.13 89.20 N/S-not sampled

Example 9 Pharmacokinetic Analysis of Ropivacaine Formulations inCanines

In a series of pharmacokinetic studies, ten dogs (5 male—5 female) weretreated with the formulations listed in Table 8-1. Dogs received theentire contents of 1 syringe containing sufficient polyorthoesterformulation to deliver approximately 100 mg of ropivacaine. Plasmasamples were taken from each dog at the following time points: −24, 1,6, 12, 24, 48, 72, 96, 120, 144, and 168 hours and frozen. The plasmasamples were subsequently analyzed by LC/MS/MS for ropivacaine. A plotof the plasma concentration of ropivacaine versus time is presented inFIG. 6 . All formulations provided measurable plasma concentrations ofropivaicaine for at least 5 days.

TABLE 9-1 Ropivcacaine Formulations Used in PK Study in CaninesFormulation Solvent Ropivacaine Ropivacaine % Ropivacaine ID ID Base %HCl % % POE Solvent Composition Form 07-03 NMP  4.75% 0.25% 75.0% 25.0%Dissolved 07-04 DMAc 20.70% 0.00% 56.4% 22.9% Suspension 07-05 NMP10.00% 0.00% 45.0% 45.0% Dissolved 07-06 NMP  4.50% 0.50% 71.0% 24.0%Dissolved

Example 10 Bupivacaine Delivery Systems Comprising an Aprotic Solvent

Compositions containing between approximately 42% to 60% polyorthoesterof formula III, between approximately 30% and 42% of an aprotic solvent,and between approximately 9% and 15% bupivacaine base were prepared. Thecomposition was prepared by first the dissolving the appropriate amountof bupivacaine base into the appropriate amount of aprotic solvent atapproximately 80° C. The drug solution was then mixed with theappropriate amount of polymer at an elevated temperature, untilhomogenous. Exemplary compositions are presented in Table 10-1.

TABLE 10-1 Bupivacaine Delivery Systems: Polyorthoester-Aprotic SolventCompositions Formulation Solvent % ID ID Drug % POE % Solvent 02-01 NMP15.0% 55.0% 30.0% 02-01 NMP 15.0% 55.0% 30.0% 02-02 NMP 15.0% 42.5%42.5% 02-03 NMP  9.5% 60.3% 30.2% 02-04 NMP  9.9% 59.3% 30.7%

Example 11 In-Vitro Release of Bupivacaine Compositions

The release of bupivacaine from the composition was determined byplacing a small amount of the polymer formulation (approximately 50 mg)into 150 mL of phosphate buffered saline. The samples were thenincubated at 37° C. without agitation. At 24 hour intervals, 1 mLsamples were taken from the vials without any agitation of the solution.Each sample was analyzed by HPLC to determine the concentration ofbupivacaine. The cumulative drug release from the 50 mg depot was thencalculated.

TABLE 11-1 In Vitro Release of Bupivacaine Percent Bupivacaine Releasedfor Compositions Composition # 24 hrs 48 hrs 72 hrs 96 hrs 168 hrs 192hrs 216 hrs 02-01 34.38 41.24 47.86 53.05 67.50 72.14 80.94 02-03 19.6624.54 31.49 NS 43.33 50.54 N/S

Example 12 Pharmacokinetic Analysis of Bupivacaine Formulations inCanines

In a series of pharmacokinetic studies, between 2 and 10 beagles weretreated with the formulations listed in Table 12-1 (Example 10). Dogsreceived the entire contents of 1 syringe containing sufficientpolyorthoester formulation to deliver approximately 100 mg ofbupivacaine. Plasma samples were taken from each dog at the followingtime points: −24, 1, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours andfrozen. The plasma samples were subsequently analyzed by LC/MS/MS forbupivacaine. A plot of the plasma concentration of bupivacaine versustime is presented in FIG. 7 . All formulations provided measurableplasma concentrations of bupivacaine for at least 5 days.

TABLE 12-1 Bupivacaine Formulations Used in PK Study in CaninesFormulation ID Solvent ID % Drug % POE % Solvent 02-01 NMP 15.0% 55.0%30.0% 02-02 NMP 15.0% 42.5% 42.5%

Example 13 Pharmacodynamic Analysis of Local Anesthetic Formulations inPigs

Two formulations, 02-01 (Example 12) and 07-03 (Example 9), wereevaluated for their capacity to reduce post-surgical incisional pain ina porcine model system. In this model, a 7 cm long skin and fasciaincision is made in the left flank under general anesthesia. Twomilliliters of test formulation was either injected into the tissuearound the wound or instilled directly into the wound while the controlgroup received saline injected around the wound (n=4 for each group).The skin incision was then closed using sterile sutures.

Post-operative pain was assessed using the Von Frey methodology. VonFrey filaments (Ugo Basile) were applied at approximately ˜0.5 cmproximal to the incision line to the surface of the flank skin.Filaments were applied until the animal withdrew from the stimuli (theact of moving away from the stimuli). Each filament was applied 3-5times. If withdrawal was not achieved, a thicker filament was applied.The maximum force filament is 60 g. If a withdrawal was achieved, athinner filament was applied (thicker or thinner refers tothicker/higher or thinner/lower gram force). By alternating the filamentthickness, the gram force required to achieve withdrawal reaction wasdetermined and recorded.

TABLE 13-1 Anesthetic Polyorthoester-Aprotic Solvent Formulations:Reduction of Post-Surgical Incisional Pain in a Porcine Model SystemGram Force Baseline 1 Hrs 3 Hrs 5 Hrs Day 1 Day 2 Day 3 Day 4 Day 5 Day6 Control 60  1.35 1.7 2   1.1 3    3.35 4.5 6.5 6.5 Saline InjectionSample 02-01 60 60   51.5  51.5  34.5  23.25 20.5  10.25 17.75 40.25Instilled Sample 02-01 60 14.25 13.75 48.75 6.5 3   8   6.5 10.25 29  Injected Sample 07-03 60 60   51.5  60   40.25 13.75 11.5  6   15  24.5  Instilled Sample 07-03 60 43   60   36.25 22.5  22   12.75 6  11.5  14.25 Injected

Example 14 Buprenorphine Delivery Systems Comprising an Aprotic Solvent

Compositions containing between 76.2% to 62.1% polyorthoester of formulaIII, prepared with 0.1% of glycolic ester R¹, between 30.0% and 42.5% ofan aprotic solvent, and between 4.9% and 15.0% buprenorphine wereprepared. The composition was prepared by first the dissolving theappropriate amount of buprenorphine into the appropriate amount ofaprotic solvent at approximately 80° C. The drug solution was then mixedwith the appropriate amount of polymer at an elevated temperature, untilhomogenous. Exemplary compositions are presented in Table 13-1.

TABLE 14-1 Buprenorphine Delivery Systems: Polyorthoester-AproticSolvent Compositions Formulation Solvent ID ID % Drug % POE % Solvent03-01 DMSO 7.23% 76.08% 18.09% 03-02 DMSO 15.00%  67.20% 17.90% 03-03NMP 6.94% 62.10% 30.99% 03-04 DMSO 4.91% 76.22% 18.86%

Example 15 In-Vitro Release of Buprenorphine Compositions

The release of buprenorphine from the composition was determined byplacing a small amount of the polymer formulation (approximately 25 mg)into 150 mL of phosphate buffered saline containing 0.05% cetyltrimethylammonium bromide. The samples were then incubated at 37° C.without agitation. At predetermined intervals, 1 mL samples were takenfrom the vials without any agitation of the solution. Each sample wasanalyzed by HPLC to determine the concentration of buprenorphine. Thecumulative drug release from the 25 mg depot was then calculated.

TABLE 15-1 In Vitro Release of Buprenorphine Composition PercentBupivacaine Released for Compositions # 1 day 6 days 15 days 22 days03-01 18 35 55 81 03-02 16 44 80 N/A 03-03 5 80 N/A N/A 03-04 5 73 N/AN/A

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

What is claimed is:
 1. A delivery system, comprising: a polyorthoester;an aprotic solvent in which the polyorthoester is miscible to form asingle phase; and a local amide- or anilide-type anesthetic dispersed orsolubilized in the single phase; wherein the anesthetic is released fromthe system over a period of between approximately 1 day andapproximately 8 weeks.
 2. The delivery system of claim 1, wherein theanesthetic is dispersed in the single phase.
 3. The delivery system ofclaim 1, wherein the anesthetic is solubilized in the single phase. 4.The delivery system of claim 1, wherein the delivery system has aviscosity of less than about 10,000 cP at 37° C.
 5. The delivery systemof claim 1, wherein the aprotic solvent is an amide or a sulfoxide. 6.The delivery system of claim 5, wherein the aprotic solvent is an amideselected from the group consisting of 2-pyrrolidone, dimethyl formamide,N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethyl acetamide,N-cyclohexyl-2-pyrrolidone and caprolactam.
 7. The delivery system ofclaim 5, wherein the aprotic solvent is a sulfoxide selected from eitherdimethyl sulfoxide or decylmethylsulfoxide.
 8. The delivery system ofclaim 1, wherein the aprotic solvent is selected from dimethylsulfoxide,dimethyl acetamide, and N-methyl pyrrolidone.
 9. The delivery system ofclaim 1, wherein the local amide- or anilide-type anesthetic is selectedfrom the group consisting of bupivacaine, levobupivacaine, dibucaine,mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
 10. Thedelivery system of claim 9, wherein the local amide- or anilide typeanesthetic is bupivacaine.
 11. The delivery system of claim 9, whereinthe local amide- or anilide type anesthetic is ropivacaine.
 12. Thedelivery system of claim 1, wherein the polyorthoester is represented bythe structure shown as Formula III,

where A is R¹ or R³, where R¹ is:

where p and q are integers that vary from between about 1 to 20 and theaverage number of p or the average of the sum of p and q is between 1and 7; R³ and R⁶ are each independently:

where x is an integer of 0 to 30; where A is R1 in 0 to 20% of themonomeric units of the polyorthoester.
 13. The delivery system of claim1, where the polyorthoester has a molecular weight between about 1,000and 10,000 daltons.
 14. The delivery system of claim 1, wherein theaprotic solvent is in an amount between 15-50 percent by weight of thedelivery system; and the local amide- or anilide-type anesthetic is inan amount between 3 and 30 percent by weight of the delivery system. 15.A method of administering a local amide- or anilide-type anesthetic,comprising dispensing from a needle a delivery system of claim
 1. 16.The method of claim 15, comprising dispensing from a needle a deliverysystem of claim
 8. 17. A method of providing local anesthesia to apatient, comprising administering to a patient the delivery system ofclaim 1 in an amount effective for reducing or preventing pain.
 18. Themethod of claim 17, wherein the administering comprises dispensing thedelivery system from a needle.
 19. The method of claim 17, wherein theadministering comprises injecting the delivery system in a region oftissue near a nerve, into an epidural space, as an intrathecalinjection, around the periphery of a surgical site or wound ordispensing directly into a surgical site or wound.
 20. The method ofclaim 17, comprising administering to the patient the delivery system ofclaim 8.